List of phenyltropanes

Phenyltropanes (PTs) are a family of chemical compounds originally derived from structural modification of cocaine. The main feature differentiating phenyltropanes from cocaine is that they lack the ester functionality at the 3-position terminating in the benzene; and thusly the phenyl is attached direct to the tropane skeleton with no further spacer (therefore the name "phenyl"-tropane) that the cocaine benzoyloxy provided. The original purpose of which was to extirpate the cardiotoxicity inherent in the local anesthetic "numbing" capability of cocaine (since the methylated benzoate ester is essential to cocaine's blockage of sodium channels which cause topical anesthesia) while retaining stimulant function.^{[lower-alpha 1]} These compounds present many different avenues of research into therapeutic applications, particularly in addiction treatment. Uses vary depending on their construction and structure-activity relationship ranging from the treating of cocaine dependency to understanding the dopamine reward system in the human brain to treating Alzheimer's & Parkinson's diseases. (Since 2008 there have been continual additions to the list and enumerations of the plethora of types of chemicals that fall into the category of this substance profile.^[2]) Certain phenyltropanes can even be used as a smoking cessation aid (c.f. RTI-29). Many of the compounds were first elucidated in published material by the Research Triangle Institute and are thus named with "RTI" serial-numbers.^{[lower-alpha 2]} Similarly, a number of others are named for Sterling-Winthrop pharmaceuticals ("WIN" serial-numbers) and Wake Forest University ("WF" serial-numbers). The following includes many of the phenyltropane class of drugs that have been made and studied.

2-Carboxymethyl esters (phenyl-methylecgonines)

Like cocaine, phenyltropanes are considered a 'typical' or 'classical' (i.e. "cocaine-like") DAT re-uptake pump ligands in that they stabilize an "open-to-out" conformation on the dopamine transporter; despite the extreme similarity to phenyltropanes, benztropine and others are in suchwise not considered "cocaine-like" and are instead considered atypical inhibitors insofar as they stabilize what is considered a more inward-facing (closed-to-out) conformational state.^[5]

Considering the differences between PTs and cocaine: the difference in the length of the benzoyloxy and the phenyl linkage contrasted between cocaine and phenyltropanes makes for a shorter distance between the centroid of the aromatic benzene and the bridge nitrogen of the tropane in the latter PTs. This distance being on a scale of 5.6 Å for phenyltropanes and 7.7 Å for cocaine or analogs with the benzoyloxy intact.^{[lower-alpha 3]} The manner in which this sets phenyltropanes into the binding pocket at MAT is postulated as one possible explanation to account for PTs increased behavioral stimulation profile over cocaine.^{[lower-alpha 4]}

Blank spacings within tables for omitted data use "no data", "?", "-" or "—" interchangeably.

2β-carbmethoxy-3β-(4′-substituted phenyl)tropanes (IC₅₀ values)
monohalogen halide-phenyltropanes (11a—11e) alkyl-, & alkenyl-phenyltropanes (11r—11x) alkynyl-phenyltropanes (11y & 11z)

Structure	Short Name i.e. Trivial IUPAC (non-systematic) Name (Singh's #)	R (para-substitution) of benzene	DA [3H]WIN 35428 IC50 nM	5HT [3H]paroxetine IC50 nM (Ki nM)	NE [3H]nisoxetine IC50 nM (Ki nM)	selectivity 5-HTT/DAT	selectivity NET/DAT
	cocaine (benzoyloxytropane)	H	102 ± 12 241 ± 18ɑ	1045 ± 89 112 ± 2b	3298 ± 293 160 ± 15c	10.2 0.5d	32.3 0.7e
	(para-hydrogen)phenyltropane WIN 35,065-2 (β-CPT) Troparil 11a	H	23 ± 5.0 49.8 ± 2.2ɑ	1962 ± 61 173 ± 13b	920 ± 73 37.2 ± 5.2c	85.3 3.5d	40.0 0.7e
	para-fluorophenyltropane WIN 35,428 (β-CFT) 11b	F	14 (15.7 ± 1.4) 22.9 ± 0.4ɑ	156 (810 ± 59) 100 ± 13b	85 (835 ± 45) 38.6 ± 9.9c	51.6 4.4d	53.2 1.7e
	para-nitrophenyltropane 11k	NO2	10.1 ± 0.10	?	?	?	?
	para-aminophenyltropane RTI-29[6] 11j	NH2	9.8 24.8 ± 1.3g	5110	151	521.4	15.4
	para-chlorophenyltropane RTI-31 11c	Cl	1.12 ± 0.06 3.68 ± 0.09ɑ	44.5 ± 1.3 5.00 ± 0.05b	37 ± 2.1 5.86 ± 0.67c	39.7 1.3d	33.0 1.7e
	para-methylphenyltropane RTI-32 Tolpane 11f	Me	1.71 ± 0.30 7.02 ± 0.30ɑ	240 ± 27 19.38 ± 0.65b	60 ± 0.53e 8.42 ± 1.53c	140 2.8d	35.1 1.2e
	para-bromophenyltropane RTI-51 Bromopane 11d	Br	1.81 (1.69) ± 0.30	10.6 ± 0.24	37.4 ± 5.2	5.8	20.7
	para-iodophenyltropane RTI-55 (β-CIT) Iometopane 11e	I	1.26 ± 0.04 1.96 ± 0.09ɑ	4.21 ± 0.3 1.74 ± 0.23b	36 ± 2.7 7.51 ± 0.82c	3.3 0.9d	28.6 3.8e
	para-hydroxyphenyltropane 11h	OH	12.1 ± 0.86	—	—	—	—
	para-methoxyphenyltropane 11i	OCH3	8.14 ± 1.3	—	—	—	—
	para-azidophenyltropane 11l	N3	2.12 ± 0.13	—	—	—	—
	para-trifluoromethylphenyltropane 11m	CF3	13.1 ± 2.2	—	—	—	—
	para-acetylaminophenyltropane 11n	NHCOCH3	64.2 ± 2.6	—	—	—	—
	para-propionylaminophenyltropane 11o	NHCOC2H5	121 ± 2.7	—	—	—	—
	para-ethoxycarbonylaminophenyltropane 11p	NHCO2C3H5	316 ± 48	—	—	—	—
	para-trimethylstannylphenyltropane 11q	Sn(CH3)3	144 ± 37	—	—	—	—
	para-ethylphenyltropane RTI-83 11g	Et	55 ± 2.1	28.4 ± 3.8 (2.58 ± 3.5)	4030 (3910) ± 381 (2360 ± 230)	0.5	73.3
	para-n-propylphenyltropane RTI-282i 11r	n-C3H7	68.5 ± 7.1	70.4 ± 4.1	3920 ± 130	1.0	57.2
	para-isopropylphenyltropane 11s	CH(CH3)2	597 ± 52	191 ± 9.5	75000 ± 5820	0.3	126
	para-vinylphenyltropane RTI-359 11t	CH-CH2	1.24 ± 0.2	9.5 ± 0.8	78 ± 4.1	7.7	62.9
	para-methylethenylphenyltropane RTI-283j 11u	C(=CH2)CH3	14.4 ± 0.3	3.13 ± 0.16	1330 ± 333	0.2	92.4
	para-trans-propenylphenyltropane RTI-296i 11v	trans-CH=CHCH3	5.29 ± 0.53	11.4 ± 0.28	1590 ± 93	2.1	300
	para-allylphenyltropane 11x	CH2CH=CH2	32.8 ± 3.1	28.4 ± 2.4	2480 ± 229	0.9	75.6
	para-ethynylphenyltropane RTI-360 11y	C≡CH	1.2 ± 0.1	4.4 ± 0.4	83.2 ± 2.8	3.7	69.3
	para-propynylphenyltropane RTI-281i 11z	C≡CCH3	2.37 ± 0.2	15.7 ± 1.5	820 ± 46	6.6	346
	para-cis-propenylphenyltropane RTI-304 11w	cis-CH=CHCH3	15 ± 1.2	7.1 ± 0.71	2,800k ± 300	0.5	186.6k
	para-(Z)-phenylethenylphenyltropane	cis-CH=CHPh	11.7 ± 1.12	—	—	—	—
	para-benzylphenyltropane	-CH2-Ph	526 ± 65	7,240 ± 390 (658 ± 35)	6670 ± 377 (606 ± 277)	13.7	12.6
	para-phenylethenylphenyltropane	CH2 ║ -C-Ph	474 ± 133	2,710 ± 800 (246 ± 73)	7,060 ± 1,760 (4,260 ± 1,060)	5.7	14.8
	para-phenylethylphenyltropanel	-(CH2)2-Ph	5.14 ± 0.63	234 ± 26 (21.3 ± 2.4)	10.8 ± 0.3 (6.50 ± 0.20)	45.5	2.1
	para-(E)-phenylethenylphenyltropanel RTI-436	trans–CH=CHPh	3.09 ± 0.75	335 ± 150 (30.5 ± 13.6)	1960 ± 383 (1180 ± 231)	108.4	634.3
	para-phenylpropylphenyltropanel	-(CH2)3-Ph	351 ± 52	1,243 ± 381 (113 ± 35)	14,200 ± 1,800 (8,500 ± 1,100)	3.5	40.4
	para-phenylpropenylphenyltropanel	-CH=CH-CH2-Ph	15.8 ± 1.31	781 ± 258 (71 ± 24)	1,250 ± 100 (759 ± 60)	49.4	79.1
	para-phenylbutylphenyltropanel	-(CH2)4-Ph	228 ± 21	4,824 ± 170 (439 ± 16)	2,310 ± 293 (1,390 ± 177)	21.1	10.1
	para-phenylethynylphenyltropanel RTI-298[7]	–≡–Ph	3.7 ± 0.16	46.8 ± 5.8 (4.3 ± 0.53)	347 ± 25 (209 ± 15)	12.6	93.7
	para-phenylpropynylphenyltropanel[8]	–C≡C-CH2Ph	1.82 ± 0.42	13.1 ± 1.7 (1.19 ± 0.42)	27.4 ± 2.6 (16.5 ± 1.6)	7.1	15
	para-phenylbutynylphenyltropanel RTI-430	–C≡C(CH2)2Ph	6.28 ± 1.25	2180 ± 345 (198 ± 31)	1470 ± 109 (885 ± 66)	347.1	234
	para-phenylpentynylphenyltropanel	–C≡C-(CH2)3-Ph	300 ± 37	1,340 ± 232 (122 ± 21)	4,450 ± 637 (2,680 ± 384)	4.46	14.8
	para-trimethylsilylethynylphenyltropane[3]	—	—	—	—	—	—
	para-hydroxypropynylphenyltropane[3]	—	—	—	—	—	—
	para-hydroxyhexynylphenyltropanel	–C≡C-(CH2)4OH	57 ± 4	828 ± 29 (75 ± 2.6)	9,500 ± 812 (5,720 ± 489)	14.5	166.6
	para-(thiophen-3-yl)phenyltropane Tamagnan[4]	p-thiophene	12	0.017	189	0.001416	15.7
	para-biphenyltropane 11aa	Ph	10.3 ± 2.6f 29.4 ± 3.8ɑ 15.6 ± 0.6	95.8 ± 36 (8.7 ± 3.3)	1,480 ± 269 (892 ± 162)	6.1	94.8
	3β-2-naphthylphenyltropane RTI-318 11bb	3β-2-naphthyl	0.51 ± 0.03 3.32 ± 0.08f 3.53 ± 0.09ɑ	0.80 ± 0.06 (0.07 ± 0.1)	21.1 ± 1.0 (12.7 ± 0.60)	1.5	41.3
	para-bimethoxyphenyltropane 15	OCH2OCH3h	—	—	—	—	—

ɑ[3H]DA uptake displacement Ki value. b[3H]5-HT uptake displacementKi value. c[3H]NE uptake displacement Ki value.

d[3H]5-HT uptake to [3H]DA uptake ratio. e[3H]NE uptake to [3H]DA uptake ratio. fIC50 for displacement of [3H]cocaine. gValues from alternate data-set differing from that used in rest of table. hOriginal source (Scheme 4, page 931, 7th of article)[1] name given for compound (bottom of first ¶) is at variance with formula in scheme on same page: i.e. "methoxymethyl" versus "methoxymethoxy"

iProtonated as the (-)—tartrate salt (isomer) jProtonated as the tartrate salt kWas cited by S. Singh as 28,000nM for SERT or a DAT/SERT ratio of 1,867. However, in Singh's paper he cited J. Med. Chem. 1996, 39, 4030, Table 1[9] which shows a ten times lower value, which is consistent with numerous RTI patents published showing the ten-× lower value. lWhereas many bulky additions to the arene unit of phenyltropanes hinder and impair affinity, it has been observed that the para-substituted rigid triple bond analogs terminating in a second phenyl (off of the initial C3 position phenyl) have a high-binding affinity, putatively attesting to the existence of another binding domain that extends beyond the usual ending point where the benzene accords to the acceptor somewhere along the length of range inhabited by the DAT, corresponding to an 180° extension outward from the para area of the aryl of these type of ligands.[8]

(4′-Monosubstituted 2,3-Thiophene phenyl)-tropanes

Tamagnan (thiophene) analogues of para-phenyltropanes.^[4]

Compound structure	Alphanumeric code (name)	para-substitution	N8	SERT	DAT	NET	Selectivity SERT versus DAT	Selectivity SERT versus NET
	1 (cocaine)	(—)-Cocaine	CH3	1050	89	3320	0.08	3.2
	2 (β-CIT), (Iometopane)	Iodo	CH3	0.46 ± 0.06	0.96 ± 0.15	2.80 ± 0.40	2.1	6.1
	(R,S-Citalopram)	—	—	1.60	16,540	6,190	10,338	3,869
	4a	2-Thiophene	CH3	0.15 ± 0.015	52 ± 12.8	158 ± 12	346	1,053
	4b (Tamagnan)	3-Thiophene	CH3	0.017 ± 0.004	12.1 ± 3	189 ± 82	710	11,118
	4c	2-(5-Br)-Thiophene	CH3	0.38 ± 0.008	6.43 ± 0.9	324 ± 19	17	853
	4d	2-(5-Cl)-Thiophene	CH3	0.64 ± 0.04	4.42 ± 1.64	311 ± 25	6.9	486
	4e	2-(5-I)-Thiophene	CH3	4.56 ± 0.84	22.1 ± 3.2	1,137 ± 123	4.9	249
	4f	2-(5-NH2)-Thiophene	CH3	64.7 ± 3.7	>10,000	>30,000	>155	>464
	4g	2-(4,5-NO2)-Thiophene	CH3	5,000	>30,000	>10,000	>6.0	>2.0
	4h	3-(4-Br)-Thiophene	CH3	4.02 ± 0.34	183 ± 69	>10,000	46	>2,488
	5a	2-Thiophene	H	0.11 ± 0.006	12.2 ± 0.9	75.3 ± 9.6	111	685
	5b	3-Thiophene	H	0.23 ± 0.02	6.4 ± 0.27	39 ± 0.8	28	170

(3′,4′-Disubstituted phenyl)-tropanes

Compound (+ S. Singh's name)	X (4′-para)	Y (3′-meta)	2 Position	config	8	DA	5-HT	NE
RTI-318 11bb	β-naphthyl		CO2Me	β,β	NMe	0.5	0.81	20
Dichloropane (RTI-111ɑ)[10] 17c	Cl	Cl	CO2Me	β,β	NMe	0.79	3.13	18.0
RTI-88 [recheck] 17e	NH2	I	CO2Me	β,β	NMe	1.35	1329c	320c
RTI-97 17d	NH2	Br	CO2Me	β,β	NMe	3.91	181	282
RTI-112b 17b	Cl	Me	CO2Me	β,β	NMe	0.82	10.5	36.2
RTI-96 17a	F	Me	CO2Me	β,β	NMe	2.95	76	520
RTI-295	Et	I	CO2Me	β,β	NMe	21.3	2.96	1349
RTI-353 (EINT)	Et	I	CO2Me	β,β	NH	331	0.69	148
RTI-279	Me	I	CO2Me	β,β	NH	5.98	1.06	74.3
RTI-280	Me	I	CO2Me	β,β	NMe	3.12	6.81	484
Meltzer[11]	catechol		CO2Me	β,β	NMe	>100	?	?
Meltzer[11]	OAc	OAc	CO2Me	β,β	NMe	?	?	?

• ^ɑas ·HCl (salt)
• ^bas ·HCl·2 H₂O (salt)
• ^cSingh gives the reverse value with respect to i.e. 1,329 for NET & 320 for 5-HT

Para-meta-substituted 2β-carbomethoxy-3α-(4′-substituted phenyl)tropanes^[1]

Compound	Short Name (S. Singh)	Y	X	DA	5HT	NE	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	meta-fluorophenyltropane 16a	F	H	23 ± 7.8	-	-	-	-
	meta-chlorophenyltropane 16b	Cl	H	10.6 ± 1.8	-	-	-	-
	meta-bromophenyltropane 16c	Br	H	7.93 ± 0.08ɑ	-	-	-	-
	meta-iodophenyltropane 16d	I	H	26.1 ± 1.7	-	-	-	-
	meta-tributylstannylphenyltropane 16e	SnBu3	H	1100 ± 170	-	-	-	-
	meta-ethynylphenyltropane[3]	C≡CH	H	-	-	-	-	-
	meta-methyl-para-fluorophenyltropane RTI-96 17a	CH3	F	2.95 ± 0.58	-	-	-	-
	meta-methyl-para-chlorophenyltropane RTI-112c 17b	CH3	Cl	0.81 ± 0.05	10.5 ± 0.05	36.2 ± 1.0	13.0	44.7
	meta-para-dichlorophenyltropane RTI-111b[10] Dichloropane 17c	Cl	Cl	0.79 ± 0.08b	3.13 ± 0.36b	18.0 ± 0.8 17.96 ± 0.85bd	4.0b	22.8b
	meta-bromo-para-aminophenyltropane RTI-97 17d	Br	NH2	3.91 ± 0.59	181	282	46.2	72.1
	meta-iodo-para-aminophenyltropane RTI-88 17e	I	NH2	1.35 ± 0.11	120 ± 4	1329 ± 124	88.9	984
	meta-iodo-para-azidophenyltropane 17f	I	N3	4.93 ± 0.32	-	-	-	-

• ^ɑIC₅₀ determined in Cynomolgous monkey caudate-putamen
• ^bas ·HCl (salt)
• ^cas ·HCl·2 H₂O (salt)
• ^dNE_N

3β-(4-alkylthio, -methylsulfinyl, and -methylsulfonylphenyl)tropanes^[12]

Structure	Compound	R	X	n	Inhibition of [3H]WIN 35,428 @ DAT IC50 (nM)	Inhibition of [3H]Paroxetine @ 5-HTT Ki (nM)	Inhibition of [3H]Nisoxetine @ NET Ki (nM)	NET/DAT (uptake ratio)	NET/5-HTT (uptake ratio)
	Cocaine	Des-thio/sulfinyl/sulfonyl H	H	Desmethyl 0	89.1	95	1990	22	21
	para-methoxyphenyltropane Singh: 11i	Des-thio/sulfinyl/sulfonyl OCH3	H	0	6.5 ± 1.3	4.3 ± 0.5	1110 ± 64	171	258
	7a	CH3	H	0	9 ± 3	0.7 ± 0.2	220 ± 10	24	314
	7b	C2H5	H	0	232 ± 34	4.5 ± 0.5	1170 ± 300	5	260
	7c	CH(CH3)2	H	0	16 ± 2	23 ± 2	129 ± 2	8	7
	7d	CF3	H	0	200 ± 70	8 ± 2	1900 ± 300	10	238
	7e	CH3	Br	0	10.1 ± 1	0.6 ± 0.2	121 ± 12	12	202
	7f	CH3	Br	1	76 ± 18	3.2 ± 0.4	690 ± 80	9	216
	7g	CH3	H	1	91 ± 16	4.3 ± 0.6	515 ± 60	6	120
	7h	CH3	H	2	>10,000	208 ± 45	>10,000	1	48

(2′,4′-Disubstituted phenyl)-tropanes

Ortho-para-substituted (2′,4′-disubstituted phenyltropanes)

Compound structure	Trivial IUPAC (non-systematic) Name	Y ortho	X para	DA	5HT	NE	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	ortho,para-dinitrophenyltropane[13]	NO2	NO2	-	-	-	-	-

(3′,4′,5′-Trisubstituted para-methoxyphenyl)-tropanes

Para-meta(3′)-meta(5′)-(di-meta)-substituted 2β-carbomethoxy-(3′,4′,5′-substituted phenyl)tropanes^[14]
Para-methoxy/(ethoxy)-meta-substituted phenyltropanes

Structure	Short Name (All compounds tested as HCl salts)	X 3′-(meta)	Y 5′-(di-meta)	OR 4′-(para)	DAT IC50 [3H](compound #)12	5-HTT Ki [3H]Paroxetine	NET Ki [3H]Nisoxetine	Selectivity NET/DAT Ratio Ki/IC50	Selectivity NET/5-HTT Ratio Ki/Ki
	Cocaine	-	-	-	89.1	95	1990	22	21
	6 RTI-112	-	-	-	0.82 ± 0.05	0.95 ± 0.04	21.8 ± 0.6	27	23
	7a 11i	H	H	CH3	6.5 ± 1.3	4.3 ± 0.5	1110 ± 64	171	258
	7b	H	H	C2H5	92 ± 8	1.7 ± 0.4	1690 ± 50	18	994
	7c	F	H	CH3	16 ± 1	4.8 ± 0.5	270 ± 50	17	56
	7d	Br	H	CH3	47 ± 15	3.1 ± 0.1	160 ± 20	3	52
	7f	Br	Br	CH3	92 ± 22	2.9 ± 0.1	4100 ± 400ɑ	45	1413
	7e	I	H	CH3	170 ± 60	3.5 ± 0.4	180 ± 20	1	51
	7 g	I	I	CH3	1300 ± 200	7.5 ± 0.8	180 ± 20	4	667

^ɑN=2

(2′,4′,5′-Trisubstituted phenyl)-tropanes

Ortho-para(4′)-meta(5′)-trisubstituted 2β-carbomethoxy-(2′,4′,5′-substituted phenyl)tropanes^[3]

Structure	Short Name	R1 2′-(ortho)	R2 4′-(para)	R3 5′-(meta)	DAT	5-HTT	NET	Selectivity NET/DAT Ratio	Selectivity NET/5-HTT Ratio
	para-ethyl-ortho, meta-diiodophenyltropane[3]	iodo	ethyl	iodo	-	-	-	-	-

2-Carbmethoxy modified (replaced/substituted)

General 2-carbmethoxy modifications

2β-substitutions of p-methoxy-phenyltropanes

Para-OCH₃-(3β-(4-Methoxyphenyl)tropane-2β-carboxylic acid ester analogues^[15]

Structure	Short Name (All compounds tested as HCl salts)	CO2R (2β-substituted) (compound 9 is 2β=R)	DAT IC50 [3H](compound #)12	5-HTT Ki [3H]Paroxetine	NET Ki [3H]Nisoxetine	Selectivity NET/DAT Ratio Ki/IC50	Selectivity NET/5-HTT Ratio Ki/Ki
	7a 11i	CH3	6.5 ± 1.3	4.3 ± 0.5	1110 ± 64	171	258
	8a	(CH3)2CH	14 ± 3	135 ± 35	2010 ± 200	144	15
	8b	cyclopropane	6.0 ± 2	29 ± 3	1230 ± 140	205	42
	8c	cyclobutane	13 ± 3	100 ± 8	>3000	231	30
	8d	O2N…1,4-xylene…(CH2)2	42 ± 8	2.9 ± 0.2	330 ± 20	8	114
	8e	H2N…1,4-xylene…(CH2)2	7.0 ± 2	8.3 ± 0.4	2200 ± 300ɑ	314	265
	8f	CH3CONH…1,4-xylene…(CH2)2	6.0 ± 1	5.5 ± 0.5	1460 ± 30	243	265
	8 g	H2N…2-bromo-1,4-dimethylbenzene…(CH2)2	3.3 ± 1.4	4.1 ± 0.6	1850 ± 90	561	451
	8h	H2N…1,3-dibromo-2,5-dimethylbenzene…(CH2)2	15 ± 6	2.0 ± 0.4	2710 ± 250ɑ	181	1360
	8i	H2N…2-iodo-1,4-dimethylbenzene…(CH2)2	2.5 ± 0.7	3.5 ± 1	2040 ± 300ɑ	816	583
	8j	H2N…1,3-diiodo-2,5-dimethylbenzene…(CH2)2	102 ± 15	1.0 ± 0.1	2600 ± 200ɑ	25	2600
	9	3-(4-methylphenyl)-1,2-oxazole	18 ± 6	860 ± 170	>3000	167	3

^ɑN=2

2β-carboxy side-chained (p-chloro/iodo/methyl) phenyltropanes

Multi-substituted structures of 2β-ester-3β-phenyltropanes^[1]

Compound	Short Name (S. Singh)	R	X	IC50 (nM) DAT [3H]WIN 35428	IC50 (nM) 5-HTT [3H]paroxetine	IC50 (nM) NET [3H]nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	23a	CH(CH3)2	H	85.1 ± 2.5	23121 ± 3976	32047 ± 1491	272	376
	23b	C6H5	H	76.7 ± 3.6	106149 ± 7256	19262 ± 593	1384	251
	24a	CH(CH3)2	Cl	1.4 ± 0.13 6.04 ± 0.31ɑ	1400 ± 7 128 ± 15b	778 ± 21 250 ± 0.9c	1000 21.2d	556 41.4e
	24b	cyclopropyl	Cl	0.96 ± 0.10	168 ± 1.8	235 ± 8.39	175	245
	24c	C6H5	Cl	1.99 ± 0.05 5.25 ± 0.76ɑ	2340 ± 27 390 ± 34b	2960 ± 220 242 ± 30c	1176 74.3d	1.3 41.6e
	24d	C6H4-4-I	Cl	32.6 ± 3.9	1227 ± 176	967.6 ± 26.3	37.6	29.7
	24e	C6H4-3-CH3	Cl	9.37 ± 0.52	2153 ± 143	2744 ± 140	230	293
	24f	C6H4-4-CH3	Cl	27.4 ± 1.5	1203 ± 42	1277 ± 118	43.9	46.6
	24 g	C6H4-2-CH3	Cl	3.91 ± 0.23	3772 ± 384	4783 ± 387	965	1223
	24h	C6H4-4-Cl	Cl	55 ± 2.3	16914 ± 1056	4883 ± 288	307	88.8
	24i	C6H4-4-OCH3	Cl	71 ± 5.6	19689 ± 1843	1522 ± 94	277	21.4
	24j	(CH2)2C6H4-4-NO2	Cl	2.71 ± 0.13	-	-	-	-
	24k	(CH)2C6H4-4-NH2	Cl	2.16 ± 0.25	-	-	-	-
	24l	(CH2)2C6H3-3-I-4-NH2	Cl	2.51 ± 0.25	-	-	-	-
	24m	(CH2)2C6H3-3-I-4-N3	Cl	14.5 ± 0.94	-	-	-	-
	24n	(CH2)2C6H4-4-N3	Cl	6.17 ± 0.57	-	-	-	-
	24o	(CH2)2C6H4-4-NCS	Cl	5.3 ± 0.6	-	-	-	-
	24p	(CH2)2C6H4-4-NHCOCH2Br	Cl	1.73 ± 0.06	-	-	-	-
	25a	CH(CH3)2	I	0.43 ± 0.05 2.79 ± 0.13ɑ	66.8 ± 6.53 12.5 ± 1.0b	285 ± 7.6 41.2 ± 3.0c	155 4.5d	663 14.8e
	25b	cyclopropyl	I	0.61 ± 0.08	15.5 ± 0.72	102 ± 11	25.4	167
	25c	C6H5	I	1.51 ± 0.34 6.85 ± 0.93ɑ	184 ± 22 51.6 ± 6.2b	3791 ± 149 32.7 ± 4.4c	122 7.5d	2510 4.8e
	26a	CH(CH3)2	CH3	6.45 ± 0.85 15.3 ± 2.08ɑ	6090 ± 488 917 ± 54b	1926 ± 38 73.4 ± 11.6c	944 59.9d	299 4.8e
	26b	CH(C2H5)2	CH3	19.1 ± 1	4499 ± 557	3444 ± 44	235	180
	26c	cyclopropyl	CH3	17.8 ± 0.76	485 ± 21	2628 ± 252	27.2	148
	26d	cyclobutyl	CH3	3.74 ± 0.52	2019 ± 133	4738 ± 322	540	1267
	26e	cyclopentyl	CH3	1.68 ± 0.14	1066 ± 109	644 ± 28	634	383
	26f	C6H5	CH3	3.27 ± 0.06 9.13 ± 0.79ɑ	24500 ± 1526 1537 ± 101b	5830 ± 370 277 ± 23c	7492 168d	1783 30.3e
	26g	C6H4-3-CH3	CH3	8.19 ± 0.90	5237 ± 453	2136 ± 208	639	261
	26h	C6H4-4-CH3	CH3	81.2 ± 16	15954 ± 614	4096 ± 121	196	50.4
	26i	C6H4-2-CH3	CH3	23.2 ± 0.97	11040 ± 504	25695 ± 1394	476	1107
	26j	C6H4-4-Cl	CH3	117 ± 7.9	42761 ± 2399	9519 ± 864	365	81.3
	26k	C6H4-4-OCH3	CH3	95.6 ± 8.8	82316 ± 7852	3151 ± 282	861	33.0

• ^ɑKi value for displacement of [³H]DA uptake.
• ^bKi value for displacement of [³H]5-HT uptake.
• ^cKi value for displacement of [³H]NE uptake.
• ^d[³H]5-HT uptake to [³H]DA uptake ratio.
• ^e[³H]NE uptake to [³H]DA uptake ratio.

Carboxyaryl

Compound	X	2 Position	config	8	DA	5-HT	NE
RTI-122	I	-CO2Ph	β,β	NMe	1.50	184	3,791
RTI-113	Cl	-CO2Ph	β,β	NMe	1.98	2,336	2,955
RTI-277	NO2	-CO2Ph	β,β	NMe	5.94	2,910	5,695
RTI-120 [recheck]	Me	-CO2Ph	β,β	NMe	3.26	24,471	5,833
RTI-116	Cl	-CO2(p-C6H4I)	β,β	NMe	33	1,227	968
RTI-203	Cl	CO2(m-C6H4Me)	β,β	NMe	9.37	2153	2744
RTI-204	Cl	-CO2(o-C6H4Me)	β,β	NMe	3.91	3,772	4,783
RTI-205	Me	-CO2(m-C6H4Me)	β,β	NMe	8.19	5,237	2,137
RTI-206	Cl	-CO2(p-C6H4Me)	β,β	NMe	27.4	1,203	1,278

2-Phenyl-3-Phenyltropanes

2-Phenyl-3-phenyltropane binding affinities and inhibition of DA & 5-HT Uptake^[1]

Compound Structure	Short Name (S. Singh)	Stereochemistry	X (para)	DAT [3H]WIN 35428 IC50 (nM)	DAT [3H]Mazindol Ki (nM)	5-HTT [3H]Paroxetine IC50 (nM)	[3H]DA uptake Ki (nM)	[3H]5-HT uptake Ki (nM)	Selectivity [3H]5-HT/[3H]DA
	Cocaine	(2β,3β)	(H)	89 ± 4.8	281	1050 ± 89	423	155	0.4
	67a	2β,3β	H	12.6 ± 1.8	14.9	21000 ± 3320	28.9	1100	38.1
	67b	2β,3α	H	-	13.8	-	11.7	753	64.3
	67c	2α,3α	H	690 ± 37	-	41300 ± 5300	-	-	-
	68	2β,3α	F	-	6.00	-	4.58	122	26.6
	69a	2β,3β	CH3	1.96 ± 0.08	2.58	11000 ± 83	2.87	73.8	25.7
	69b	2β,3α	CH3	-	2.87	-	4.16	287	69.0
	69c	2α,3α	CH3	429 ± 59	-	15800 ± 3740	-	-	-

Carboxyalkyl

Code	X	2 Position	config	8	DA	5-HT	NE
RTI-77	Cl	CH2C2(3-iodo-p-anilino)	β,β	NMe	2.51	—	2247
RTI-121 IPCIT	I	-CO2Pri	β,β	NMe	0.43	66.8	285
RTI-153	I	-CO2Pri	β,β	NH	1.06	3.59	132
RTI-191	I	-CO2Prcyc	β,β	NMe	0.61	15.5	102
RTI-114	Cl	-CO2Pri	β,β	NMe	1.40	1,404	778
RTI-278	NO2	-CO2Pri	β,β	NMe	8.14	2,147	4,095
RTI-190	Cl	-CO2Prcyc	β,β	NMe	0.96	168	235
RTI-193	Me	-CO2Prcyc	β,β	NMe	1.68	1,066	644
RTI-117	Me	-CO2Pri	β,β	NMe	6.45	6,090	1,926
RTI-150	Me	-CO2Bucyc	β,β	NMe	3.74	2,020	4,738
RTI-127	Me	-CO2C(H)Et2	β,β	NMe	19	4500	3444
RTI-338	ethyl	-CO2C2Ph	β,β	NMe	1104	7.41	3366

Use of a cyclopropyl ester appears to enable better MAT retention than does the choice of isopropyl ester.

Use of a ^cycBu resulted in greater DAT selectivity than did the ^cycPr homologue.

2-Alkyl Esters & Ethers

Esters (2-Alkyl)

2β-Alkyl Ester Phenyltropanes^[1]

Structure	Short Name (S. Singh)	2β=R	Ki (nM) DAT [3H]WIN 35428	IC50 (nM) [3H]DA uptake	Selectivity uptake/binding
	59a	CH=CHCO2CH3	22 ± 2	123 ± 65	5.6
	59b	CH2CH2CO2CH3	23 ± 2	166 ± 68	7.2
	59c	(CH2)2CH=CHCO2CH3	20 ± 2	203 ± 77	10.1
	59d	(CH22)4CO2CH3	30 ± 2	130 ± 7	4.3
	59e	CH=CHCH2OH	26 ± 3	159 ± 43	6.1
	59f	CH2CH2CH2OH	11 ± 1	64 ± 32	5.8
	59g	CH2CH2COC6H5	28 ± 2	47 ± 15	1.7

Ethers (2-Alkyl)

2-Alkyl Ether Phenyltropanes^[1]

Molecular Structure	Short Name (S. Singh)	Stereochemistry	DAT [3H]WIN 35428 IC50 (nM)	5-HTT [3H]Paroxetine IC50 (nM)	NET [3H]Nisoxetine IC50 (nM)	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	Paroxetine		623 ± 25	0.28 ± 0.02	535 ± 15	0.0004	0.8
	R-60a	2β,3β	308 ± 20	294 ± 18	5300 ± 450	0.9	17.2
	R-60b	2α,3β	172 ± 8.8	52.9 ± 3.6	26600 ± 1200	0.3	155
	R-60c	2β,3α	3.01 ± 0.2	42.2 ± 16	123 ± 9.5	14.1	40.9
	S-60d	2β,3β	1050 ± 45	88.1 ± 2.8	27600 ± 1100	0.08	26.3
	S-60e	2α,3β	1500 ± 74	447 ± 47	2916 ± 1950	0.3	1.9
	S-60f	2β,3α	298 ± 17	178 ± 13	12400 ± 720	0.6	41.6

Carboxamides

U.S. Patent 5,736,123

Structure	Code (S. Singh #)	X	2 Position	config	8	DA [3H]WIN 35428 (IC50 nM)	NE [3H]nisoxetine	5-HT [3H]paroxetine (IC50 nM)	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	RTI-106 27b	Cl	CON(H)Me	β,β	NMe	12.4 ± 1.17	1584 ± 62	1313 ± 46	106	128
	RTI-118 27a	Cl	CONH2	β,β	NMe	11.5 ± 1.6	4270 ± 359	1621 ± 110	141	371
	RTI-222 29d	Me	morpholinyl	β,β	NMe	11.7 ± 0.87	23601 ± 1156	>100K	>8547	2017
	RTI-129 27e	Cl	CONMe2	β,β	NMe	1.38 ± 0.1	942 ± 48	1079 ± 102	792	683
	RTI-146 27d	Cl	CONHCH2OH	β,β	NMe	2.05 ± 0.23	144 ± 3	97.8 ± 10	47.7	70.2
	RTI-147 27i	Cl	CON(CH2)4	β,β	NMe	1.38 ± 0.03	3,950 ± 72	12400 ± 1207	8985	2862
	RTI-156	Cl	CON(CH2)5	β,β	NMe	6.61	5832	3468
	RTI-170	Cl	CON(H)CH2C≡CH	β,β	NMe	16.5	1839	4827
	RTI-172	Cl	CON(H)NH2	β,β	NMe	44.1	3914	3815
	RTI-174	Cl	CONHCOMe	β,β	NMe	158	>43K	>125K
	RTI-182	Cl	CONHCH2COPh	β,β	NMe	7.79	1722	827
	RTI-183✲ 27 g	Cl	CON(OMe)Me	β,β	NMe	0.85 ± 0.06	549 ± 18.5	724 ± 94	852	646
	RTI-186 29c	Me	CON(OMe)Me	β,β	NMe	2.55 ± 0.43	422 ± 26	3402 ± 353	1334	165
	RTI-198 27h	Cl	CON(CH2)3	β,β	NMe	6.57 ± 0.67	990 ± 4.8	814 ± 57	124	151
	RTI-196 27c	Cl	CONHOMe	β,β	NMe	10.7 ± 1.25	9907 ± 632	43700 ± 1960	4084	926
	RTI-201	Cl	CONHNHCOPh	β,β	NMe	91.8	>20K	>48K
	RTI-208 27j	Cl	CONO(CH2)3	β,β	NMe	1.47 ± 0.13	1083 ± 76	2470 ± 56	1680	737
	RTI-214 27l	Cl	CON(-CH2CH2-)2O	β,β	NMe	2.90 ± 0.3	8545 ± 206	88769 ± 1855	30610	2946
	RTI-215 27f	Cl	CONEt2	β,β	NMe	5.48 ± 0.19	5532 ± 299	9433 ± 770	1721	1009
	RTI-217	Cl	CONH(m-C6H4OH)	β,β	NMe	4.78	>30K	>16K
	RTI-218✲	Cl	CON(Me)OMe	β,β	NMe	1.19	520	1911
	RTI-226 27 m	Cl	CONMePh	β,β	NMe	45.5 ± 3	2202 ± 495	23610 ± 2128	519	48.4
	RTI-227	I	CONO(CH2)3	β,β	NMe	0.75	446	230
	RTI-229[16] 28a	I	CON(CH2)4	β,β	NMe	0.37 ± 0.04	991 ± 21	1728 ± 39	4670	2678
	27k					6.95 ± 1.21	1752 ± 202	3470 ± 226	499	252
	28b					1.08 ± 0.15	103 ± 6.2	73.9 ± 8.1	68.4	95.4
	28c					0.75 ± 0.02	357 ± 42	130 ± 15.8	173	476
	29a					41.8 ± 2.45	4398 ± 271	6371 ± 374	152	105
	29b					24.7 ± 1.93	6222 ± 729	33928 ± 2192	1374	252

✲RTI-183 and RTI-218 suggest possible copy-error, seeing as "CON(OMe)Me" & "CON(Me)OMe" difference between methyl & methoxy render as the same.

2β-Carboxamide-3β-Phenyltropanes^[1]

Compound	Short Name (S. Singh)	R	X	IC50 (nM) DAT [3H]WIN 35428	IC50 (nM) 5-HTT [3H]Paroxetine	IC50 (nM) NET [3H]Nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	29a	NH2	CH3	41.8 ± 2.45	6371 ± 374	4398 ± 271	152	105
	29b	N(CH2CH3)2	CH3	24.7 ± 1.93	33928 ± 2192	6222 ± 729	1374	252
	29c	N(OCH3)CH3	CH3	2.55 ± 0.43	3402 ± 353	422 ± 26	1334	165
	29d	4-morpholine	CH3	11.7 ± 0.87	>100000	23601 ± 1156	>8547	2017

Heterocycles

These heterocycles are sometimes referred to as the "bioisosteric equivalent" of the simpler esters from which they are derived. A potential disadvantage of leaving the ββ-ester unreacted is that in addition to being hydrolyzable, it can also epimerize^[17] to the energetically more favorable trans configuration. This can happen to cocaine also.

Several of the oxadiazoles contain the same number and types of heteroatoms, while their respective binding potencies display 8×-15× difference. A finding that would not be accounted for by their affinity originating from hydrogen bonding.

To explore the possibility of electrostatic interactions, the use of molecular electrostatic potentials (MEP) were employed with model compound 34 (replacing the phenyltropane moiety with a methyl group). Focusing on the vicinity of the atoms @ positions A—C, the minima of electrostatic potential near atom position A (ΔV_min(A)), calculated with semi-empirical (AM1) quantum mechanics computations (superimposing the heterocyclic and phenyl rings to ascertain the least in the way of steric and conformational discrepancies) found a correlation between affinity @ DAT and ΔV_min(A): wherein the values for the latter for 32c = 0, 32 g = -4, 32h = -50 & 32i = -63 kcal/mol.

In contrast to this trend, it is understood that an increasingly negative ΔV_min is correlated with an increase of strength in hydrogen bonding, which is the opposing trend for the above; this indicates that the 2β-substituents (at least for the heterocyclic class) are dominated by electrostatic factors for binding in-the-stead of the presumptive hydrogen bonding model for this substituent of the cocaine-like binding ligand.^{[lower-alpha 5]}

3-Substituted-isoxazol-5-yl

N-methylphenyltropanes with 1R β,β stereochemistry.

Code (S.S. #)	X	R	DA	NE	5HT
RTI-165	Cl	3-methylisoxazol-5-yl	0.59	181	572
RTI-171	Me	3-methylisoxazol-5-yl	0.93	254	3818
RTI-180	I	3-methylisoxazol-5-yl	0.73	67.9	36.4
RTI-177 β-CPPIT 32 g	Cl	3-phenylisoxazol-5-yl	1.28 ± 0.18	504 ± 29	2420 ± 136
RTI-176	Me	3-phenylisoxazol-5-yl	1.58	398	5110
RTI-181	I	3-phenylisoxazol-5-yl	2.57	868	100
RTI-184	H	methyl	43.3	—	6208
RTI-185	H	Ph	285	—	>12K
RTI-334	Cl	3-ethylisoxazol-5-yl	0.50	120	3086
RTI-335	Cl	isopropyl	1.19	954	2318
RTI-336	Cl	3-(4-methylphenyl)isoxazol-5-yl	4.09	1714	5741
RTI-337	Cl	3-t-butyl-isoxazol-5-yl	7.31	6321	37K
RTI-345	Cl	p-chlorophenyl	6.42	5290	>76K
RTI-346	Cl	p-anisyl	1.57	762	5880
RTI-347	Cl	p-fluorophenyl	1.86	918	7257
RTI-354	Me	3-ethylisoxazol-5-yl	1.62	299	6400
RTI-366	Me	R = isopropyl	4.5	2523 (1550)	42,900 (3900)
RTI-371	Me	p-chlorophenyl	8.74	>100K (60,200)	>100K (9090)
RTI-386	Me	p-anisyl	3.93	756 (450)	4027 (380)
RTI-387	Me	p-fluorophenyl	6.45	917 (546)	>100K (9400)

3-Substituted-1,2,4-oxadiazole

Heterocyclic (N-methyl)phenyltropanes with 1R stereochemistry.

Structure	Code (Singh's #)	X	R	DAT (IC50 nM) displacement of [H3]WIN 35428	NET (IC50 nM) [H3]nisoxetine	5-HTT (IC50 nM) [H3]paroxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	ααRTI-87	H	3-methyl-1,2,4-oxadiazole	204	36K	30K
	βαRTI-119	H	3-methyl-1,2,4-oxadiazole	167	7K	41K
	αβRTI-124	H	3-methyl-1,2,4-oxadiazole	1028	71K	33K
	RTI-125 (32a)	Cl	3-methyl-1,2,4-oxadiazole	4.05 ± 0.57	363 ± 36	2584 ± 800	637	89.6
	ββRTI-126[18] (31)	H	3-methyl-1,2,4-oxadiazole	100 ± 6	7876 ± 551	3824 ± 420	38.3	788
	RTI-130 (32c)	Cl	3-phenyl-1,2,4-oxadiazole	1.62 ± 0.02	245 ± 13	195 ± 5	120	151
	RTI-141 (32d)	Cl	3-(p-anisyl)-1,2,4-oxadiazole	1.81 ± 0.19	835 ± 8	337 ± 40	186	461
	RTI-143 (32e)	Cl	3-(p-chlorophenyl)-1,2,4-oxadiazole	4.06 ± 0.22	40270 ± 180 (4069)	404 ± 56	99.5	9919
	RTI-144 (32f)	Cl	3-(p-bromophenyl)-1,2,4-oxadiazole	3.44 ± 0.36	1825 ± 170	106 ± 10	30.8	532
	βRTI-151 (33)	Me	3-phenyl-1,2,4-oxadiazole	2.33 ± 0.26	60 ± 2	1074 ± 130	459	25.7
	αRTI-152	Me	3-phenyl-1,2,4-oxadiazole	494	—	1995
	RTI-154 (32b)	Cl	3-isopropyl-1,2,4-oxadiazole	6.00 ± 0.55	135 ± 13	3460 ± 250	577	22.5
	RTI-155	Cl	3-cyclopropyl-1,2,4-oxadiazole	3.41	177	4362

N-methylphenyltropanes with 1R β,β stereochemistry.

Structure	Code	X	2 Group	DAT (IC50 nM) displacement of [H3]WIN 35428	NET (IC50 nM) displacement of [H3]nisoxetine	5-HTT (IC50 nM) displacement of [H3]paroxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	RTI-157	Me	tetrazole	1557	>37K	>43K
	RTI-163	Cl	tetrazole	911	—	5456
	RTI-178	Me	5-phenyl-oxazol-2-yl	35.4	677	1699
	RTI-188	Cl	5-phenyl-1,3,4-oxadiazol-2-yl	12.6	930	3304
	RTI-189 (32i)	Cl	5-phenyl-oxazol-2-yl	19.7 ± 1.98	496 ± 42	1120 ± 107	56.8	25.5
	RTI-194	Me	5-methyl-1,3,4-oxadiazol-2-yl	4.45	253	4885
	RTI-195	Me	5-phenyl-1,3,4-oxadiazol-2-yl	47.5	1310	>22,000
	RTI-199	Me	5-phenyl-1,3,4-thiadiazol-2-yl	35.9	>24,000	>51,000
	RTI-200	Cl	5-phenyl-1,3,4-thiadiazol-2-yl	15.3	4142	>18,000
	RTI-202	Cl	benzothiazol-2-yl	1.37	403	1119
	RTI-219	Cl	5-phenylthiazol-2-yl	5.71	8516	10,342
	RTI-262	Cl
	RTI-370	Me	3-(p-cresyl)isoxazol-5-yl	8.74	6980	>100K
	RTI-371	Cl	3-(p-chlorophenyl)isoxazol-5-yl	13	>100K	>100K
	RTI-436	Me	-CH=CHPh[20]	3.09	1960 (1181)	335 (31)
	RTI-470	Cl	o-Cl-benzothiazol-2-yl	0.094	1590 (994)	1080 (98)
	RTI-451	Me	benzothiazol-2-yl	1.53	476 (287)	7120 (647)
	32g			1.28 ± 0.18	504 ± 29	2420 ± 136	1891	394
	32h			12.6 ± 10.3	929 ± 88	330 ± 196	262	73.7

Above is taken from: RTI, Kuhar, et al. U.S. Patent 5,935,953 (1999).

N.B There are some alternative ways of making the tetrazole ring however; C.f. the sartan drugs synthesis schemes. Bu₃SnN₃ is a milder choice of reagent than hydrogen azide (c.f. Irbesartan).

Acyl (C2-propanoyl)

# (#)	X	Y	2 Position	config	8	DA	5-HT	NE
WF-23 (39n)	β-naphthyl		C(O)Et	β,β	NMe	0.115	0.394	No data
WF-31 PIT	-Pri	H	C.O.Et	β,β	NMe	615	54.5	No data
WF-11✲ PTT (39e)	Me	H	-C.O.Et	β,β	NMe	8.2	131	No data
WF-25 (39a)	H	H	-C.O.Et	β,β	NMe	48.3	1005	No data
WF-33	6-MeoBN		C(O)Et	α,β	NMe	0.13	2.24	No data
✲Compound WF-11 has been shown, under consistent exposure, to elicit a biological response opposite of cocaine i.e. tyrosine hydroxylase gene expression down-regulation (instead of up-regulation as has been observed to be the case for chronic cocaine administration)

2β-acyl-3β-phenyltropane structures^{[lower-alpha 6]}

Structure	S. Singh's alphanumeric assignation (name)	R1	R2	DAT [125I]RTI-55 IC50 (nM)	5-HTT [3H]Paroxetine Ki (nM)	Selectivity 5-HTT/DAT
	cocaine			173 ± 19	—	—
	Troparil 11a (WIN 35065-2)			98.8 ± 12.2	—	—
	WF-25 39a	C2H5	C6H5	48.3 ± 2.8	1005 ± 112	20.8
	39b	CH3	C6H5	114 ± 22	1364 ± 616	12.0
	39c	C2H5	C6H4-4-F	15.3 ± 2.8	630 ± 67	41.2
	39d	CH3	C6H4-4-F	70.8 ± 13	857 ± 187	12.1
	WF-11 39e	C2H5	C6H4-4-CH3	8.2 ± 1.6	131 ± 1	16.0
	(+)-39e	C2H5	C6H4-4-CH3	4.21 ± 0.05	74 ± 12	17.6
	(-)-39e	C2H5	C6H4-4-CH3	1337 ± 122	>10000	—
	39f	CH3	C6H4-4-CH3	9.8 ± 0.5	122 ± 22	12.4
	39g	CH3	C6H4-4-C2H5	152 ± 24	78.2 ± 22	0.5
	39h	C2H5	C6H4-4-CH(CH3)2	436 ± 41	35.8 ± 4.4	0.08
	39i	C2H5	C6H4-4-C(CH3)3	2120 ± 630	1771 ± 474	0.8
	39j	C2H5	C6H4-4-C6H5	2.29 ± 1.08	4.31 ± 0.01	1.9
	39k	C2H5	C6H4-2-CH3	1287 ± 322	710000	>7.8
	39l	C2H5	1-naphthyl	5.43 ± 1.27	20.9 ± 2.9	3.8
	39m	CH3	1-naphthyl	10.1 ± 2.2	25.6 ± 5.1	2.5
	WF-23 39n	C2H5	2-naphthyl	0.115 ± 0.021	0.394 ± 0.074	3.5
	39o	CH3	2-naphthyl	0.28 ± 0.11	1.06 ± 0.36	3.8
	39p	C2H5	C6H4-4-CH(C2H5)2	270 ± 38	540 ± 51	2.0
	39q	C2H5	C6H4-4-C6H11	320 ± 55	97 ± 12	0.30
	39r	C2H5	C6H4-4-CH=CH2	0.90 ± 0.34	3.2 ± 1.3	3.5
	39s	C2H5	C6H4-4-C(=CH2)CH3	7.2 ± 2.1	0.82 ± 0.38	0.1

2β-Acyl-3β-naphthyl substituted

2β-Acyl-3β-(substituted naphthyl)-8-azabicyclo[3.2.1]octanes^[22]

Structure	Short Assignation (Numeric code, Davies UB)	R	DAT [125H]RTI-55ɑ IC50 nM	SERT [3H]paroxetineb Ki nM	NET [3H]nisoxetinec Ki nM	potency ratio SERT/DAT	potency ratio SERT/NET
	WF-11 (6)	4′-Me	8.2 ± 1.6	131 ± 10	65 ± 9.2	0.06	0.5
	WF-31 (7)	4′-iPr	436 ± 41	36 ± 4	>10,000	12	>250
	WF-23 (8)	2-naphthalene	0.12 ± 0.02	0.39 ± 0.07	2.9 ± 0.5	0.3	7
	2β-acyl-3β-1-naphthalene (9a)	4′-H	5.3 ± 1.3	21 ± 2.9	49 ± 10	0.3	18
	(9b)	4′-Me	25.1 ± 0.5	8.99 ± 1.70	163 ± 36	3	18
	(9c)	4′-Et	75.1 ± 11.9	175 ± 25	4769 ± 688	0.7	27
	(9d)	4′-iPr	225 ± 36	136 ± 64	>10,000	2	>73.5
	(10a)	6′-Et	0.15 ± 0.04	0.38 ± 0.19	27.7 ± 9.6	0.4	74
	(10b)	6′-iPr	0.39 ± 0.04	1.97 ± 0.33	no data	0.2	—
	(10ce)	6′- OMe	0.13 ± 0.04	2.24 ± 0.34	no data	0.05	—
	(10d)	5′-Et, 6′-OMe	30.8 ± 6.6	7.55 ± 1.57	3362 ± 148	4.1	445
	(10e)	5′-C(Me)=CH2, 6′-OMe	45.0 ± 3.7	88.0 ± 13.3	2334 ± 378	0.5	26.5
	(10f)	6′-I	0.35 ± 0.07	0.37 ± 0.02	no data	1.0	—
	(10g)	7′-I	0.45 ± 0.05	0.47 ± 0.02	no data	0.5d	—
	(10h)	5′-NO2, 6′-OMe	148 ± 50	15 ± 1.6	no data	10	—
	(10i)	5′-I, 6′-OMe	1.31 ± 0.33	2.27 ± 0.31	781 ± 181	0.6	344
	(10j)	5′-COMe, 6′-OMe	12.6 ± 3.8	15.8 ± 1.65	498 ± 24	0.8	32
	(11a)	2β-COCH3, 1-naphthyl	10 ± 2.2	26 ± 5.1	165 ± 40	0.4	6.3
	(11b)	2α-COCH3, 1-naphthyl	97 ± 21	217 ± 55	no data	0.45	—
	(11c)	2α-COCH2CH3, 2-naphthyl	2.51 ± 0.82	16.4 ± 2.0	68.0 ± 10.8	0.15	4.1
	(11d)	2β-COCH3, 2-naphthyl	1.27 ± 0.15	1.06 ± 0.36	4.9 ± 1.2	1.2	4.6
	(11e)	2β-COCH(CH3)2, 2-naphthyl	0.25 ± 0.08	2.08 ± 0.80	37.6 ± 10.5	0.12	18.1
	(11f)	2β-COCH2CH3, 2-naphthyl, N8-demethyl	0.03 ± 0.01	0.23 ± 0.07	2.05 ± 0.9	0.13	8.9

ɑ nonspecific binding was determined in the presence of 1.0 μM WF-23 (source equates WF-23 as analogue 3a, but table gives # as analogue 8) b nonspecific binding was determined in the presence of 10.0 μM fluoxetine

c nonspecific binding was determined in the presence of 1.0 μM desipramine d ratio shown as halved; a possible copy-error due to closeness to 1:1 of other indicated values e sources differ on whether C2 position acyl is alpha or beta configured

Ester reduction

Note: p-fluorophenyl is weaker than the others. RTI-145 is not peroxy, it is a methyl carbonate.

Code	X	2 Position	config	8	DA	5-HT	NE
RTI-100	F	-CH2OH	β,β	NMe	47	4741	no data
RTI-101	I	-CH2OH	β,β	NMe	2.2	26	no data
RTI-99	Br	-CH2OH	β,β	NMe	1.49	51	no data
RTI-93	Cl	-CH2OH	β,β	NMe	1.53	204	43.8
RTI-105	Cl	-CH2OAc	β,β	NMe	1.60	143	127
RTI-123	Cl	-CH2OBz	β,β	NMe	1.78	3.53	393
RTI-145	Cl	-CH2OCO2Me	β,β	NMe	9.60	2.93	1.48

2-Alkane/Alkene

2-Alkane/Alkene-3-Phenyltropanes

Structure	Singh's #	R	X	DAT mazindol displacement	DA uptake	5-HT Uptake	Selectivity DA uptake/DAT binding
	11a WIN 35062-2			89.4	53.7	186	0.6
	11c			0.83 ± 00.7	28.5 ± 0.9	—	34.3
	11f			5.76	6.92	23.2	1.2
	41a	(CH2)2CH3	H	12.2	6.89	86.8	0.6
	41b	(CH2)3C6H5	H	16 ± 2a	43 ± 13b	—	2.7
	42	(CH2)2CH3	F	5.28	1.99	21.7	0.4
	43a	CH=CH2	Cl	0.59 ± 0.15	2.47 ± 0.5	—	4.2
	43b	E-CH=CHCl	Cl	0.42 ± 0.04	1.13 ± 0.27	—	2.7
	43c	Z-CH=CHCl	Cl	0.22 ± 0.02	0.88 ± 0.05	—	4.0
	43d	E-CH=CHC6H5	Cl	0.31 ± 0.04	0.66 ± 0.01	—	2.1
	43e	Z-CH=CHC6H5	Cl	0.14 ± 0.07	0.31 ± 0.09	—	2.2
	43f	CH2CH3	Cl	2.17 ± 0.20	2.35 ± 0.52	—	1.1
	43 g	(CH2)2CH3	Cl	0.94 ± 0.08	1.08 ± 0.05	—	1.1
	43h	(CH2)3CH3	Cl	1.21 ± 0.18	0.84 ± 0.05	—	0.7
	43i	(CH2)5CH3	Cl	156 ± 15	271 ± 3	—	1.7
	43j	(CH2)2C6H5	Cl	1.43 ± 0.03	1.54 ± 0.08	—	1.0
	44a	(CH2)2CH3	CH3	1.57	1.10	10.3	0.7
	44b	(CH2)3CH3	CH3	1.82	1.31	15.1	0.7
	45	(CH2)2CH3	H	74.9	30.2	389	0.4
	46	(CH2)2CH3	F	21.1	12.1	99.6	0.6
	47a	(CH2)2CH3	CH3	8.91	11.8	50.1	1.3
	47b	(CH2)3CH3	CH3	11.4	10.1	51.0	0.9

^aK_i value for displacement of WIN 35428.
^bIC₅₀ value.

Irreversible covalent (cf. ionic) C2 ligands

Irreversible (phenylisothiocyanate) binding ligand (Murthy, V.; Martin, T. J.; Kim, S.; Davies, H. M. L.; Childers, S. R. (2008). "In Vivo Characterization of a Novel Phenylisothiocyanate Tropane Analog at Monoamine Transporters in Rat Brain". Journal of Pharmacology and Experimental Therapeutics. 326 (2): 587–595. doi:10.1124/jpet.108.138842. PMID 18492949. )^[23] RTI-76:^[24] 4′-isothiocyanatophenyl (1R,2S,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate. Also known as: 3β-(p-chlorophenyl)tropan-2β-carboxylic acid p-isothiocyanatophenylmethyl ester.

C2 Acyl, N8 phenylisothiocyanate

HD-205 (Murthy et al., 2007)^[25]

Note the contrast to the phenylisothiocyanate covalent binding site locations as compared to the one on p-Isococ, a non-phenyltropane cocaine analogue.

Benztropine based (C2-position hetero-substituted) phenyltropanes

Benztropine phenyltropane^[26][27]

F&B series (Biotin side-chains etc.)

One patent claims a series of compounds with biotin-related sidechains are pesticides.^[18]

Images of the biotin C2 side-chained phenyltropanes, click to

Code	para-X	C2-Tropane Position	config	DA	NE	5-HT
RTI-224	Me	F1c	β,β	4.49	—	155.6
RTI-233	Me	F2	β,β	4.38	516	73.6
RTI-235	Me	F3 d	β,β	1.75	402	72.4
RTI-236	Me	B1 d	β,β	1.63	86.8	138
RTI-237	Me	B2 d	β,β	7.27	258	363
RTI-244	Me	B3 d	β,β	15.6	1809	33.7
RTI-245	Cl	F4 c	β,β	77.3	—	—
RTI-246	Me	F4 c	β,β	50.3	3000	—
RTI-248	Cl	F6 c	β,β	9.73	4674	6.96
RTI-249	Cl	F1 c	β,β	8.32	5023	81.6
RTI-266	Me	F2	β,β	4.80	836	842
RTI-267	Me	F7 wrong	β,β	2.52	324	455
RTI-268	Me	F7 right	β,β	3.89	1014	382
RTI-269	Me	F8	β,β	5.55	788	986

C2 + C3 (side-chain) fused (carboxylate & benzene conjoined)

(1R,2S,10R,12S)-15-methyl-15-azatetracyclo(10.2.1.0²,¹⁰.0⁴,⁹)pentadeca-4(9),5,7-trien-3-one^[3]

C2 linked dimers of phenyltropanes

As per Frank Ivy Carroll's patent.^[3]

Miscellany (i.e. Misc./Miscellaneous) C2-substituents

Code	X	2 Position	config	8	DA	5-HT	NE
RTI-102	I	CO2H	β,β	NMe	474	1928	43,400
RTI-103	Br	CO2H	β,β	NMe	278	3070	17,400
RTI-104	F	CO2H	β,β	NMe	2744	>100K	>100K
RTI-108	Cl	-CH2Cl	β,β	NMe	2.64	98	129.8
RTI-241	Me	-CH2CO2Me	β,β	NMe	1.02	619	124
RTI-139	Cl	-CH3	β,β	NMe	1.67	85	57
RTI-161	Cl	-C≡N	β,β	NMe	13.1	1887	2516
RTI-230	Cl	H3C–C=CH2	β,β	NMe	1.28	57	141
RTI-240	Cl	-CHMe2	β,β	NMe	1.38	38.4	84.5
RTI-145	Cl	-CH2OCO2Me	β,β	NMe	9.60	2,932	1,478
RTI-158	Me	-C≡N	β,β	NMe	57	5095	1624
RTI-131	Me	-CH2NH2	β,β	NMe	10.5	855	120
RTI-164	Me	-CH2NHMe	β,β	NMe	13.6	2246	280
RTI-132	Me	-CH2NMe2	β,β	NMe	3.48	206	137
RTI-239	Me	-CHMe2	β,β	NMe	0.61	114	35.6
RTI-338	Et	-CO2CH2Ph	β,β	NMe	1104	7.41	3366
RTI-348	H	-Ph	β,β	NMe	28.2	>34,000	2670

C2-truncated/descarboxyl (non-ecgonine w/o 2-position-replacement tropanes)

Aryl-Tropenes

WO2004113297 

Test compound	DA-uptake IC50(μM)	NA-uptake IC50(μM)	5-HT-uptake IC50(μM)
(+)-3-(4-Chlorophenyl)-8-H-aza-bicyclo[3.2.1]oct-2-ene	0.26	0.028	0.010
(+)-3-Napthalen-2-yl-8-azabicyclo[3.2.1]oct-2-ene	0.058	0.013	0.00034
(–)-8-Methyl-3-(naphthalen-2-yl)-8-azabicylo[3.2.1]oct-2-ene	0.034	0.018	0.00023

WO 9713770 

8-AZABICYCLO[3.2.1]OCT-2-ENE DERIVATIVES

Test Compound	DA uptake IC50(μM)	NE uptake IC50(μM)	5-HT uptake IC50(μM)
(±)-3-(3,4-Dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene	0.079	0.026	0.0047

U.S. Patent 2,001,047,028

Test Compound	DA uptake IC50(μM)	NE uptake IC50(μM)	5-HT uptake IC50(μM)
(±)-3-(4-cyanophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene	18	4.9	0.047
(±)-3-(4-nitrophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene	1.5	0.5	0.016
(±)-3-(4-trifluoromethoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene	22.00	8.00	0.0036

3-Aryl bicyclo[3.2.1]octanes^[1]

Structure	Compound # (S. Singh)	DAT (IC50 nM) displacement of [H3]WIN 35428	5-HTT (IC50 nM) [H3]Citalopram	Selectivity 5-HTT/DAT
	R/S-98a	7.1 ± 1.7	5160 ± 580	726
	R/S-98b	9.6 ± 1.8	33.4 ± 0.6	3.5
	R/S-98c	14.3 ± 1.1	180 ± 65	12.6

Pseudotropinearylethers

U.S. Patent 4,861,889

Enantioselective nonstandard configurations (non-2β-,3β-)

β,α Stereochemistry

Structure	Compound (RTI #) (S. Singh's #)	X	2 Group	config	8	DAT IC50 (nM) [3H]WIN 35428	5-HTT IC50 (nM) [3H]paroxetine	NET IC50 (nM) [3H]nisoxetine	selectivity 5-HTT/DAT	selectivity NET/DAT
	RTI-140 20a	H	CO2Me	β,α	NMe	101 ± 16	5,701 ± 721	2,076 ± 285	56.4	20.6
	RTI-352ɑ 20d	I	CO2Me	β,α	NMe	2.86 ± 0.16	64.9 ± 1.97	52.4 ± 4.9	22.8	18.4
	RTI-549	Br	CO2Me	β,α	NMe	—	—	—	—	—
	RTI-319b	BN	CO2Me	β,α	NMe	1.1	11.4	70.2	—	—
	RTI-286c 20b	F	CO2Me	β,α	NMe	21 ± 0.57	5062 ± 485	1231 ± 91	241	58.6
	RTI-274d	F	CH2O(3′,4′-MD-phenyl)	β,α	NH	3.96	5.62	14.4	—	—
	RTI-287	Et	CO2Me	β,α	NMe	327	1687	17,819	—	—
	20c	Cl	CO2Me	β,α	NMe	2.4 ± 0.2	998 ± 120	60.1 ± 2.4	416	25.0
	20e	Me	CO2Me	β,α	NMe	10.2 ± 0.08	4250 ± 422	275 ± 24	417	27.0
	RTI-319	3α-2-naphthyl	CO2Me	β,α	NMe	1.1 ± 0.09	11.4 ± 1.3	70.2 ± 6.28	—	—

^ɑU.S. Patent 6,358,492^bU.S. Patent 7,011,813^cU.S. Patent 7,011,813^dU.S. Patent 7,291,737

α,β Stereochemistry

CA 2112084 

Compound	DA (μM)	M.E.D. (mg/kg)	Dose (mg/kg)	Activity	Activity
(2R,3S)-2-(4-chlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane	0.39	<1	50	0	0
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(2-naphthyl)-8-azabicyclo[3.2.1]octane	0.1	1	25	0	0
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane	0.016	0.25	50	+	+++

di-chloro; para- & meta- in tandem (α,β configured phenyltropanes)

U.S. Patent 2,001,047,028

Compound	X	2 Group	config	8	DA	5-HT	NE
Brasofensine	Cl2	methyl aldoxime	α,β	NMe	—	—	—
Tesofensine	Cl2	ethoxymethyl	α,β	NMe	65	11	1.7
NS-2359 (GSK-372,475)	Cl2	Methoxymethyl	α,β	NH	—	—	—

fumaric acid salts (of α,β configured phenyltropanes)

A1 WO 2004072075 A1 

Test Compound	DA uptake IC50(μM)	NE uptake IC50(μM)	5-HT uptake IC50(μM)
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt	0.062	0.035	0.00072
(2R,3S)-2-(Naphthaleneoxymethane)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt	0.062	0.15	0.0063
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt	0.10	0.048	0.0062
(2R,3S)-2-(Naphthlyloxymethane)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt	0.088	0.051	0.013

Arene equivalent alterations

η⁶-3β-(transition metal complexed phenyl)tropanes

Unlike metal complexed PTs created with the intention of making useful radioligands, 21a & 21b were produced seeing as their η⁶-coordinated moiety dramatically altered the electronic character and reactivity of the benzene ring, as well as such a change adding asymmetrical molecular volume to the otherwise planar arene ring unit of the molecule.^[1] (cf. the Dewar–Chatt–Duncanson model)

21a was twice as potent as both cocaine and troparil in displacement of β-CFT, as well as displaying high & low affinity K_i values in the same manner as those two compounds. Whereas its inhibition of DA uptake showed it as comparably equipotent to cocaine & troparil. 21b by contrast had a one hundredfold decrease in high-affinity site binding compared to cocaine and a potency 10× less for inhibiting DA uptake.

The discrepancy in binding for the two benzene metal chelates is assumed to be due to electrostatic differences rather than their respective size difference. The solid cone angles, measured by the steric parameter (i.e. θ) is θ=131° for Cr(CO)₃ whereas Cp*Ru was θ=187° or only 30% larger. The tricarbonyl moiety being considered equivalent to the cyclopenta dienyl (Cp) ligand.^[1]

Displacement of Receptor-Bound [³H]WIN 35428 and Inhibition of [³H]DA Uptake by Transition Metal Complexes of 3β-Phenyltropanes^[1]

Structure	Compound # (S. Singh) Systematic name	Ki (nM)ɑ	IC50 (nM)	selectivity binding/uptake
	Cocaine	32 ± 5 388 ±221	405	12.6
	11a	33 ± 17 314 ± 222	373	11.3
	21ac	17 ± 15b 224 ± 83	418	24.6
	21bd	2280 ± 183	3890	1.7

• ^ɑThe binding data fit a two-site model better than a one-site model
• ^bThe K_i value for the one-site model was 124 ± 10 nM
• ^cIUPAC: [η⁶-(2β-carbomethoxy-3β-phenyl)tropane]tricarbonylchromium
• ^dIUPAC: [η⁵-(pentamethylcyclopentadienyl)]-[η⁶-(2β-carbomethoxy-3β-phenyl)tropane]ruthenium-(II) triflate

3-(2-thiophene) and 3-(2-furan)

U.S. Patent 7,247,643

Code	Compound	DA (μM)	NE (μM)	5-HT (μM)
1	(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt	0.30	0.0019	0.00052
2	(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt	0.36	0.0036	0.00042
3	(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt	0.31	0.00090	0.00036
4	(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt	0.92	0.0030	0.00053
5	(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt	0.074	0.0018	0.00074
6	(2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt	0.19	0.0016	0.00054

Thiophenyltropanes

Diaryl

Fluoxetine homologue,[28] also: Hanna et al. (2007)[29] cf. the paroxetine homologue PTs

ZIENT:[30]

6/7-tropane position substituted

2β-carbmethoxy 6/7 substituted

6/7-Substituted 2-carbomethoxy-phenyltropanes^[1]

Structure	Compound # (S. Singh)	Substitution	DAT (IC50 nM) displacement of [H3]WIN 35428	5-HTT (IC50 nM) [H3]Citalopram	Selectivity 5-HTT/DAT
	Cocaine	H	65 ± 12	-	-
	103a	3β,2β, 7-OMe 3′,4′-Cl2	86 ± 4.7	884 ± 100	10.3
	103b	3β,2β, 7-OH 3′,4′-Cl2	1.42 ± 0.03	28.6 ± 7.8	20.1
	103c	3α,2β, 7-OH 3′,4′-Cl2	1.19 ± 0.16	1390 ± 56	1168
	104a	3β,2β, 6-OH 4′-Me	215ɑ	-	-
	104b	3β,2α, 6-OH 4′-Me	15310ɑ	-	-
	104c	3α,2β, 6-OH 4′-Me	930ɑ	-	-
	104d	3α,2α, 6-OH 4′-Me	7860ɑ	-	-

• ^ɑIC₅₀ value for displacement of [H³]mazindol. IC₅₀ for cocaine 288 nM for displacement of [H³]mazindol

3-butyl 6/7 substituted

6/7-Substituted 3-butyl-phenyltropanes^[1]

Structure	Compound # (S. Singh)	Substituent	Ki nM displacement of [H3]mazindol binding	Ki nM [H3]DA uptake	Selectivity uptake/binding
	Cocaine	H	270 ± 0.03	400 ± 20	1.5
	121a	7β-CN	2020 ± 10	710 ± 40	0.3
	121b	6β-CN	3040 ± 480	6030 ± 880	2.0
	121c	7β-SO2Ph	4010 ± 310	8280 ± 1340	2.1
	121d	6β-SO2Ph	4450 ± 430	8270 ± 690	1.8
	121e	7α-OH	830 ± 40	780 ± 60	0.9
	121f	H	100 ± 10	61 ± 10	0.6
	121 g	7β-CN	24000 ± 3420	32100 ± 8540	1.3
	121h	6β-CN	11300 ± 1540	26600 ± 3330	2.3
	121i	7β-SO2Ph	7690 ± 2770	7050 ± 450	0.9
	121j	6β-SO2Ph	4190 ± 700	8590 ± 1360	2.0
	121k	7α-SO2Ph	3420 ± 1100	-	-
	121l	7β-SO2Ph, 7α-F	840 ± 260	2520 ± 290	3.0
	121 m	7α-F	200 ± 10	680 ± 10	3.4
	121n	7β-F	500 ± 10	550 ± 140	1.1

intermediate 6- & 7-position synthesis modified phenyltropanes

6/7-synthetic intermediates^[1]

Structure	Compound # (S. Singh)	Substituent W	Substituent X	Substituent Y	Substituent Z
	(±)-122a	CN	H	H	H
	(±)-122b	H	H	CH	H
	(±)-122c	H	CH	H	H
	(±)-122d	H	H	H	CH
	(±)-122e	SO2Ph	H	H	H
	(±)-122f	H	H	SO2Ph	H
	(±)-122g	H	SO2Ph	H	H
	(±)-122h	SO2Ph	F	H	H
	(±)-122i	F	SO2Ph	H	H
	(±)-122j	H	H	SO2Ph	F

8-tropane (bridgehead) position modified

Nortropanes (N-demethylated)

NS2359 (GSK-372,475)

It is well established that electrostatic potential around the para position tends to improve MAT binding. This is believed to also be the case for the meta position, although it is less studied. N-demethylation dramatically potentiates NET and SERT affinity, but the effects of this on DAT binding are insignificant.^[31] Of course, this is not always the case. For an interesting exception to this trend, see the Taxil document. There is ample evidence suggesting that N-demethylation of alkaloids occurs naturally in vivo via a biological enzyme. The fact that hydrolysis of the ester leads to inactive metabolites means that this is still the main mode of deactivation for analogues that have an easily metabolised 2-ester substituent. The attached table provides good illustration of the effect of this chemical transformation on MAT binding affinities. N.B. In the case of both nocaine and pethidine, N-demethyl compounds are more toxic and have a decreased seizure threshold.^[32]

Selected ββ Nortropanes

Code (S.S. #)	X para (unless position otherwise given inline)	DA	5HT	NE
RTI-142 75b	F	4.39	68.6	18.8
RTI-98 75d Norɑ-RTI-55	I	0.69	0.36	11.0
RTI-110 75c	Cl	0.62	4.13	5.45
RTI-173 75f	Et	49.9	8.13	122
RTI-279 Norɑ-RTI-280	para-Me meta-I	5.98 ± 0.48	1.06 ± 0.10	74.3 ± 3.8
RTI-305 Norɑ-RTI-360/11y	Ethynyl	1.24 ± 0.11	1.59 ± 0.2	21.8 ± 1.0
RTI-307 Norɑ-RTI-281/11z	Propynyl	6.11 ± 0.67	3.16 ± 0.33	115.6 ± 5.1
RTI-309 Norɑ-11t	Vinyl	1.73 ± 0.05	2.25 ± 0.17	14.9 ± 1.18
RTI-330 Norɑ-11s	Isopropyl	310.2 ± 21	15.1 ± 0.97	—
RTI-353	para-Et meta-I	330.54 ± 17.12	0.69 ± 0.07	148.4 ± 9.15

^ɑThe N-demethylated variant of (i.e. compound code-name after dash)

N-demethylating various β,β p-HC-phenyltropanes

N-Me compound code# → N-demethylated derivative compound code #	para-X	[3H]Paroxetine	[3H]WIN 35,428	[3H]Nisoxetine
11 g→75f	Ethyl	28.4 → 8.13	55 → 49.9	4,029 → 122
11t→75i	vinyl	9.5 → 2.25	1.24 → 1.73	78 → 14.9
11y→75n	Ethynyl	4.4 → 1.59	1.2 → 1.24	83.2 → 21.8
11r→75 g	1-Propyl	70.4 → 26	68.5 → 212	3,920 → 532
11v→75k	trans-propenyl	11.4 → 1.3	5.29 → 28.6	1,590 → 54
11w→75l	cis-propenyl	7.09 → 1.15	15 → 31.6	2,800 → 147
11x→75 m	Allyl	28.4 → 6.2	32.8 → 56.5	2,480 → 89.7
11z→75o	1-Propynyl	15.7 → 3.16	2.37 → 6.11	820 → 116
11s→75h	i-Propyl	191 → 15.1	597 → 310	75,000 → ?
11u→75j	2-Propenyl	3.13 → 0.6	14.4 → 23	1,330? → 144

N-Demethylating phenyltropanes to find a NRI

Isomer	4′	3′	NE	DA	5HT
β,β	Me	H	60 → 7.2	1.7 → 0.84	240 → 135
β,β	F	H	835 → 18.8	15.7 → 4.4	760 → 68.6
β,β	Cl	H	37 → 5.45	1.12 → 0.62	45 → 4.13
β,α	Me	H	270 → 9	10.2 → 33.6	4250 → 500
β,α	F	H	1200 → 9.8	21 → 32.6	5060 → 92.4
β,α	Cl	H	60 → 5.41	2.4 → 3.1	998 → 53.3
β,α	F	Me	148 → 4.23	13.7 → 9.38	1161 → 69.8
β,α	Me	F	44.7 → 0.86	7.38 → 9	1150 → 97.4

"Interest in NET selective drugs continues as evidenced by the development of atomoxetine, manifaxine, and reboxetine as new NET selective compounds for treating ADHD and other CNS disorders such as depression" (FIC, et al. 2005).^[33]

N-norphenyltropanes^[1]

Structure	Short Name (S. Singh)	Para-X	DAT [3H]WIN 35428 IC50 (nM)	5-HTT [3H]Paroxetine IC50 (nM)	NET [3H]Nisoxetine IC50 (nM)	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	Norcocaine	H	206 ± 29	127 ± 13	139 ± 9	0.6	0.7
	75a	H	30.8 ± 2.3	156 ± 8	84.5 ± 7.5	5.1	2.7
	75b	F	4.39 ± 0.20	68.6 ± 2.0	18.8 ± 0.7	15.6	4.3
	75c	Cl	0.62 ± 0.09	4.13 ± 0.62	5.45 ± 0.21	6.7	8.8
	75d	I	0.69 ± 0.2	0.36 ± 0.05	7.54 ± 3.19	0.5	10.9
	75e	para-I & 2β-CO2CH(CH3)2	1.06 ± 0.12	3.59 ± 0.27	132 ± 5	3.4	124
	75f	C2H5	49.9 ± 7.3	8.13 ± 0.30	122 ± 12	0.2	2.4
	75g	n-C3H7	212 ± 17	26 ± 1.3	532 ± 8.1	0.1	2.5
	75h	CH(CH3)2	310 ± 21	15.1 ± 0.97	-	0.05	-
	75i	CH=CH2	1.73 ± 0.05	2.25 ± 0.17	14.9 ± 1.18	1.3	8.6
	75j	C-CH3 ║ CH2	23 ± 0.9	0.6 ± 0.06	144 ± 12	0.03	6.3
	75k	trans-CH=CHCH3	28.6 ± 3.1	1.3 ± 0.1	54 ± 16	0.04	1.9
	75l	cis-CH=CHCH3	31.6 ± 2.2	1.15 ± 0.1	147 ± 4.3	0.04	4.6
	75m	CH2CH=CH2	56.5 ± 56	6.2 ± 0.3	89.7 ± 9.6	0.1	1.6
	75n	CH≡CH	1.24 ± 0.11	1.59 ± 0.2	21.8 ± 1.0	1.3	17.6
	75o	CH≡CCH3	6.11 ± 0.67	3.16 ± 0.33	116 ± 5.1	0.5	19.0
	75pɑ	3,4-Cl2	0.66 ± 0.24	1.4b	-	2.1	-

^ɑThese values determined in Cynomolgus monkey caudate-putamen ^bThe radioligand used for 5-HTT was [³H]citalopram

2β-Propanoyl-N-norphenyltropanes^[1]

Compound Structure	Short Name (S. Singh)	DAT [125I]RTI-55 IC50 (nM)	5-HTT [3H]Paroxetine Ki (nM)	NET [3H]Nisoxetine Ki (nM)	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	79a	0.07 ± 0.01	0.22 ± 0.16	2.0 ± 0.09	3.1	28.6
	79b	4.7 ± 0.58	19 ± 1.4	5.5 ± 2.0	4.0	1.2
	79c	380 ± 110	5.3 ± 1.0	3400 ± 270	0.01	8.9
	79d	190 ± 17	150 ± 50	5100 ± 220	0.8	26.8
	79e	490 ± 120	85 ± 16	4300 ± 1100	0.1	8.8
	79f	1.5 ± 1.1	0.32 ± 0.06	10.9 ± 1.5	0.2	7.3
	79g	16 ± 4.9	0.11 ± 0.02	94 ± 18	0.07	5.9

Paroxetine homologues

cf. di-aryl phenyltropanes for another SSRI approximated hybrid: the fluoxetine based homologue of the phenyltropane class.

2-(3,4-(Methylenedioxy)phenoxy)methyl-norphenyltropane binding potencies^[1]

Compound Structure	Short Name (S. Singh)	Stereochemistry	DAT [3H]WIN 35428 IC50 (nM)	5-HTT [3H]Paroxetine IC50 (nM)	NET [3H]Nisoxetine IC50 (nM)	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	Paroxetine	-	623 ± 25	0.28 ± 0.02	535 ± 15	0.0004	0.8
	R-81a	2β,3β	835 ± 90	480 ± 21	37400 ± 1400	0.6	44.8
	R-81b	2α,3β	142 ± 13	90 ± 3.4	2500 ± 250	0.6	17.6
	R-81c	2β,3α	3.86 ± 0.2	5.62 ± 0.2	14.4 ± 1.3	1.4	3.7
	S-81d	2β,3β	1210 ± 33	424 ± 15	17300 ± 1800	0.3	14.3
	S-81e	2α,3β	27.6 ± 2.4	55.8 ± 5.73	1690 ± 150	2.0	61.2
	S-81f	2β,3α	407 ± 33	19 ± 1.8	1990 ± 176	0.05	4.9

N-replaced (S,O,C)

The eight position nitrogen has been found to not be an exclusively necessary functional anchor for binding at the MAT for phenyltropanes and related compounds. Sulfurs, oxygens, and even the removal of any heteroatom, leaving only the carbon skeleton of the structure at the bridged position, still show distinct affinity for the monoamine transporter cocaine-target site and continue to form an ionic bond with a measurable degree of reasonable efficacy.

Compound	X	2 Group	config	8	DA	5-HT	NE
Tropoxane	Cl,Cl	CO2Me	(racemic) β,β	O	3.3	6.5	No data
O-4210[34]	p-F	3-methyl-5-isoxazole	β,β	S	7.0	>1000	No data

8-Oxanortropanes, binding inhibition using monkey caudate-putamen^[1]

Structure	Compound # (S. Singh)	Para- (meta-)	DAT (IC50 nM) displacement of [H3]WIN 35428	5-HTT (IC50 nM) [H3]Citalopram	Selectivity 5-HTT/DAT
	R/S-90a	H	>1000	>1000	-
	R/S-90b	F	546	2580	4.7
	R/S-90c	Cl	10	107	10.7
	R/S-90d	Br	22	30	1.4
	R/S-90e	I	7	12	1.7
	R/S-90f	3,4-Cl2	3.35	6.52	1.9
	R-90g	3,4-Cl2	3.27	4.67	1.4
	S-90h	3,4-Cl2	47	58	1.2
	R/S-91a	H	1990	11440	5.7
	R/S-91b	F	>1000	>10000	-
	R/S-91c	Cl	28.5	816	28.6
	R/S-91d	Br	9	276	30.7
	R/S-91e	I	42	72	1.7
	R/S-91f	3,4-Cl2	3.08	64.5	20.9
	R-91g	3,4-Cl2	2.34	31	13.2
	S-91h	3,4-Cl2	56	2860	51.1

N-alkyl

Compound	X	2 Group	config	8	DAT	SERT	NET
FP-β-CPPIT	Cl	3′-phenylisoxazol-5′-yl	β,β	NCH2CH2CH2F	-	-	-
FE-β-CPPIT	Cl	(3′-phenylisoxazol-5′-yl)	β,β	NCH2CH2F	-	-	-
Altropane (IACFT)	F	CO2Me	β,β	NCH2CH=CHF	-	-	-
FECNT[35]	I	CO2Me	β,β	NCH2CH2F	-	-	-
RTI-310 U.S. Patent 5,736,123	I	CO2Me	β,β	N-Prn	1.17	-	-
RTI-311	I	CO2Me	β,β	NCH2CH=CH2	1.79	-	-
RTI-312 U.S. Patent 5,736,123	I	CO2Me	β,β	NBun	0.76	-	-
RTI-313 U.S. Patent 5,736,123	I	CO2Me	β,β	NCH2CH2CH2F	1.67	-	-
Ioflupane (FP-CIT)	¹²³I	CO2Me	β,β	NCH2CH2CH2F	-	-	-
PE2I[35]	Me	CO2Me	β,β	NCH2CH=CHI	-	-	-
RTI-251	Cl	CO2Me	β,β	NCH2CO2Et	1.93	10.1	114
RTI-252	Cl	CO2Me	β,β	NCH2CH2CO2Et	2.56	35.2	125
RTI-242	Cl	β,β (bridged) -C(O)CH(CO2Me)CH2N			7.67	227	510

Bi- and tri-cyclic aza compounds and their uses U.S. Patent 6,150,376 WO 0007994 

N-substituted 3β-phenylnortropanes^[1]
(including N-phthalimidoalkyl analogues of β-CIT)

Structure	Short Name (S. Singh)	Nitrogen side-chain (N8)	DAT [3H]GBR 12935 Ki (nM)	5-HTT [3H]Paroxetine Ki (nM)	NET [3H]Nisoxetine Ki (nM)	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	Cocaine	H	350 ± 80	>10000	>30000	>28.6	-
	GBR 12909	0.06 ± 0.02	52.8 ± 4.4	>20000	880	-
	WIN 35428 11b	H	14.7 ± 2.9	181 ± 21	635 ± 110	12.3	43.2
	RTI-55 11e	H	1.40 ± 0.20	0.46 ± 0.06	2.80 ± 0.40	0.3	2
	82a	CH2CH=CH2	22.6 ± 2.9ɑ	-	-	-	-
	82b	CH2CH2CH3	43.0 ± 17.7ɑ	-	-	-	-
	82c	CH2C6H5	58.9 ± 1.65b	1073c	-	18.2	-
	82d	(CH2)3C6H5	1.4 ± 0.2b	133 ± 7c	-	95.0	-
	82e	(CH2)5C6H5	3.4 ± 0.83b	49.9 ± 10.2c	-	14.7	-
	83a	CH2CH2CH2F	1.20 ± 0.29	48.7 ± 8.4	10000	40.6	8333
	83b	CH2CH2F	4.40 ± 0.35	21.7 ± 8.3	>10000	4.9	-
	84a	CH2CH2CH2F	3.50 ± 0.39	0.110 ± 0.02	63.0 ± 4.0	0.03	18
	84b	CH2CH2F	4.00 ± 0.73	0.140 ± 0.02	93.0 ± 17.0	0.03	23.2
	84c	CH2CHF2	15.1 ± 3.7	9.6 ± 1.5	>5000	0.6	-
	84d	CH2CH2CH2Cl	3.10 ± 0.57	0.32 ± 0.06	96.0 ± 29.0	0.1	31.0
	84e	CH2CH2CH2Br	2.56 ± 0.57	0.35 ± 0.08	164 ± 47	0.1	64.1
	84f	CH2CH2CH2I	38.9 ± 6.3	8.84 ± 0.53	5000	0.2	128
	84g	CH2...methylcyclopropane	4.30 ± 0.87	1.30 ± 0.25	198 ± 9.6	0.3	46.0
	84h	CH2CH2CH2OH	5.39 ± 0.21	2.50 ± 0.20	217 ± 19	0.5	40.2
	84i	CH2CH2(OCH3)2	6.80 ± 1.10	1.69 ± 0.09	110 ± 7.7	0.2	16.2
	84j	CH2CO2CH3	11.9 ± 1.4	0.81 ± 0.10	29.1 ± 1.0	0.07	2.4
	84k	CH2CON(CH3)2	12.2 ± 3.8	6.40 ± 1.70	522 ± 145	0.5	42.8
	84l	CH2CH2CH2OMs	36.3 ± 2.1	17.3 ± 1.2	5000	0.5	138
	84m	COCH(CH3)2	2100 ± 140	102 ± 23	>10000	0.05	-
	84n	(CH2)2Pht	4.23 ± 0.48	0.84 ± 0.02	441 ± 66.0	0.2	104
	84o	(CH2)3Pht	9.10 ± 1.10	0.59 ± 0.07	74.0 ± 11.6	0.06	8.1
	84p	(CH2)4Pht	2.38 ± 0.22	0.21 ± 0.02	190 ± 18.0	0.09	79.8
	84q	(CH2)5Pht	2.40 ± 0.17	0.34 ± 0.03	60.0 ± 3.10	0.1	25.0
	84r	(CH2)8Pht	2.98 ± 0.30	0.20 ± 0.02	75.0 ± 3.6	0.07	25.2
	84sd	CH2CH=CH-CH3	15 ± 1	75 ± 5	400 ± 80	5.0	26.7
	84td	CH2C(Br)=CH2	30 ± 5	200 ± 40	>1000	6.7	-
	84ud	CH2CH=CH2I(E)	30 ± 5	960 ± 60	295 ± 33	32.0	9.8
	84vd	CH2C≡CH	14 ± 1	100 ± 30	>1000	7.1	-
	84wd	CH2C6H5	42 ± 12	100 ± 17	600 ± 100	2.4	14.3
	84xd	CH2C6H4-2-CH3	93 ± 19	225 ± 40	>1000	2.4	-
	85ad	para-H	113 ± 41	100 ± 20	>1000	0.9	-
	85bd	para-Cl, meta-Cl	29 ± 4	50 ± 6	500 ± 120	1.7	17.2
	85cd	para-Me	17 ± 7	500 ± 30	>1000	29.4	-
	85dd	para-CH(CH3)2	500 ± 120	450 ± 80	>1000	0.9	-
	85ed	para-n-C3H7	500 ± 100	300 ± 12	750 ± 160	0.6	1.5

• ^ɑIC₅₀ for displacement of [³H]cocaine. IC₅₀ for cocaine = 67.8 ± 8.7 (nM)
• ^bIC₅₀ values for displacement of [³H]WIN 35428
• ^cIC₅₀ values for displacement of [³H]citalopram
• ^dThe standard K_i value for the displacement of [³H]GBR 12935, [³H]paroxetine, and [³H]nisoxetine were 27 ± 2, 3 ± 0.2, and 80 ± 28 nM, respectively, for these experiments

3β-(4-alkylthiophenyl)nortropanes^[12]

Structure	Compound	R1	R2	Inhibition of [3H]WIN 35,428 @ DAT IC50 (nM)	Inhibition of [3H]Paroxetine @ 5-HTT Ki (nM)	Inhibition of [3H]Nisoxetine @ NET Ki (nM)	NET/DAT (uptake ratio)	NET/5-HTT (uptake ratio)
	7a	CH3	CH3	9 ± 3	0.7 ± 0.2	220 ± 10	24	314
	7b	C2H5	CH3	232 ± 34	4.5 ± 0.5	1170 ± 300	5	260
	8a	CH3	H	28 ± 6	0.19 ± 0.01	21 ± 6	0.8	110
	8b	C2H5	H	177 ± 62	1.26 ± 0.05	118 ± 13	0.7	94
	9a	CH3	FCH2CH2CH2	112 ± 2	3 ± 1	960 ± 100	9	320
	9b	C2H5	FCH2CH2CH2	1,200 ± 200	27 ± 2	>2,000	2	74
	10a	CH3	CH2=CH2CH2	71 ± 25	5.5 ± 0.8	2,000 ± 500	28	364
	10b	C2H5	CH2=CH2CH2	1,100 ± 100	47 ± 3	>2,000	2	43
	11a	CH3	CH3CH2CH2	74 ± 20	5.7 ± 0.6	1,200 ± 140	16	211
	11b	C2H5	CH3CH2CH2	900 ± 300	49 ± 6	>2,000	2	41

Tricyclic/N-constrained (inclu. N-bridged/fused/tethered)

3β-replaced (front-bridged phenyltropanes)

Constrained tropane:^[36][37]

Compound	X	Y	R	SERT Ki (nM)	DAT Ki (nM)	NET Ki (nM)
1	Cl	Cl	CH2OCOMe	1.6	1870	638
2	Br	Cl	CO2Me	2.3	5420	459
3	I	Cl	CH2OCOPh	0.06	>10K	>10K

p-methyl front & back bridged (phenyltropanes)

U.S. Patent 6,150,376

Activity at monoamine transporters: Binding Affinities & MAT Inhibition of Bridged Phenyltropanes K_i (nM)

Compound # (S. Singh's #)	2β=R	[3H]Mazindol binding	[3H]DA uptake	[3H]5-HT uptake	[3H]NE uptake	selectivity [3H]5-HT/[3H]DA
cocaine	CO2CH3	375 ± 68	423 ± 147	155 ± 40	83.3 ± 1.5	0.4
(–)-40 (–)-128		54.3 ± 10.2	60.3 ± 0.4	1.76 ± 0.23	5.24 ± 0.07	0.03
(+)-40 (+)-128		79 ± 19	114 ± 28	1.48 ± 0.07	4.62 ± 0.31	0.01
(±)-40 (±)-128		61.7 ± 8.5	60.3 ± 0.4	2.32 ± 0.23	2.69 ± 0.12	0.04
29β		620	1420	8030	—	—
30β		186	492	97.7	—	—
31β		47.0	211	28.5	—	—
29α		4140	20100	3920	—	—
30α		3960	8850	696	1150	—
45 129		6.86 ± 0.43	24.0 ± 1.3	1.77 ± 0.04	1.06 ± 0.03	0.07
42a 131a	n-Bu	4.00 ± 0.07	2.23 ± 0.12	14.0 ± 0.6	2.99 ± 0.17	6.3
41a 130a	n-Bu	17.2 ± 1.13	10.2 ± 1.4	78.9 ± 0.9	15.0 ± 0.4	7.8
42b 131b	Et	3.61 ± 0.43	11.3 ± 1.1	25.7 ± 4.3	4.43 ± 0.01	2.3
50a 133a	n-Bu	149 ± 6	149 ± 2	810 ± 80	51.7 ± 12	5.4
49a 132a	n-Bu	13.7 ± 0.8	14.2 ± 0.1	618 ± 87	3.84 ± 0.35	43.5
(–)-4		10500	16500	1890	70900	—
(+)-4		18500	27600	4630	38300	—
(–)-5		9740	9050	11900	4650	—
(+)-5		6770	10500	25100	4530	—
RTI-4229-242	N8/2β-C(O)CH(CO2Me)CH2N para-chloro	—	7.67 ± 0.31ɑ	226.54 ± 27.37b	510.1 ± 51.4c	—

• ^ɑValue for displacement of [³H]WIN 35,428 binding @ DAT
• ^bValue for displacement of [³H]paroxetine binding to SERT
• ^cValue for displacement of [³H]nisoxetine from NET

Fused tropane-derivatives as neurotransmitter reuptake inhibitors. Singh notes that all bridged derivatives tested displayed 2.5—104 fold higher DAT affinity than cocaine. The ones 2.8—190 fold more potent at DAT also had increased potency at the other two MAT sites (NET & SERT); NET having 1.6—78× increased activity. (+)-128 additionally exhibited 100× greater potency @ SERT, whereas 132a & 133a had 4—5.2× weaker 5-HTT (i.e. SERT) activity. Front-bridged (e.g. 128 & 129) had a better 5-HT/DA reuptake ratio in favor of SERT, while the back-bridged (e.g. 130—133) preferred placement with DAT interaction.^[1] U.S. Patent 5,998,405

3,4-Cl₂ front-bridged phenyltropanes

Fused Tropane: NeuroSearch A/S, Scheel-Krüger et al. U.S. Patent 5,998,405

Code	Compound	DA (μM)	NE (μM)	5-HT (μM)
1	(1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11 -one O-methyl-oxime	0.012	0.0020	0.0033
2	(1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11-one	0.18	0.035	0.0075
3	(1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one O-methyl-oxime	0.0160	0.0009	0.0032
4	(1 S,2S,4S,7R)-2-(3,4-Dichloro-phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11-ol	0.0750	0.0041	0.0028
5	(1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one	0.12	0.0052	0.0026
6	(1 S,3S,4S,8R)-3-(3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]-decan-5-ol	0.25	0.0074	0.0018
7	(1S,3S,4S,8R)-3- (3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]dec- 5-yl acetate	0.21	0.0061	0.0075
8	(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-5-methoxy-7- azatricyclo[5.3.0.04,8]decane	0.022	0.0014	0.0001

1. 1-Chloroethyl chloroformate is used to remove N-methyl of trans-aryltropanes.
2. 2° amine is reacted with Br(CH₂)nCO₂Et.
3. Base used to abstract proton α- to CO₂Et group and complete the tricyclic ring closure step (Dieckmann cyclization).

To make a different type of analog (see Kozikowski patent above)

1. Remove N-Me
2. Add ɣ-bromo-chloropropane
3. Allow for cyclization with K₂CO₃ base and KI cat.

Cycloalkane-ring alterations of the tropane ring system

Azanonane (outer ring extended)

3-Phenyl-9-azabicyclo[3.3.1]nonane derivatives

To better elucidate the binding requirements at MAT, the methylene unit on the tropane was extended by one to create the azanonane analogs.^{[lower-alpha 7]} Which are the beginning of classes of modifications that start to become effected by the concerns & influences of macrocyclic stereocontrol.

Despite the loosened flexibility of the ring system, nitrogen constrained variants (such as were created to make the bridged class of phenyltropanes) which might better fit the rigid placement necessary to suit the spatial requirements needed in the binding pocket were not synthesized. Though front-bridged types were synthesized for the piperidine homologues: the trend of equal values for either isomers of that type followed the opposing trend of a smaller and lessened plasticity of the molecule to contend with a rationale for further constraining the pharmacophore within that scope. Instead such findings lend credence to the potential for the efficacy of fusing the nitrogen on an enlarged tropane, as like upon the compounds given below.

[3.3.1]azanonane analogues
displacement of bound [³H]WIN 35428^[1]

Structure	Compound # (S. Singh)	Ki (nM)
	Cocaine	32 ± 5 390 ± 220
	WIN 35065-2	33 ± 17 310 ± 220
	146a	4600 ± 510
	146b	5730 ± 570
	146c	3450 ± 310
	146d	3470 ± 350
	147	13900 ± 2010

Azabornane (outer ring contracted)

3-Phenyl-7-azabicyclo[2.2.1]heptane derivatives

Ring-contracted analogs of phenyltropanes did not permit sufficient penetration of the phenyl into the target binding site on MAT for an affinity in the efficacious range. The distance from the nitrogen to the phenyl centroid for 155a was 4.2 and 155c was 5.0 Å, respectively. (Whereas troparil was 5.6 & compound 20a 5.5 angstroms). However piperidine homologues (discussed below) had comparable potencies.^{[lower-alpha 8]}

Azabornanes with longer substitutions at the 3β-position (benzoyloxys alkylphenyls, carbamoyls etc.) or with the nitrogen in the position it would be on the piperidine homologues (i.e. arrangements of differing locations for the nitrogens being either distal or proximal within the terms required to facilitate the framework of the compound to a correlative proportion, functional for the given moiety), were not synthesized, despite conclusions that the nitrogen to phenyl length was the issue at variance enough to be the interfering factor for the proper binding of the compressed topology of the azabornane. Carroll, however, has listed benzoyloxy azabornanes in patents.^[3]

[2.2.1]azabornane analogues
displacement of bound [³H]WIN 35428^[1]

Structure	Compound # (S. Singh)	Ki (nM)
	Cocaine	32 ± 5 390 ± 220
	WIN 35065-2	33 ± 17 310 ± 220
	155a	60,400 ± 4,800
	155b	96,500 ± 42
	155c	5,620 ± 390
	155d	18,900 ± 1,700

Piperidine homologues (inner two-carbon bridge excised)

Piperidine homologues had comparable affinity & potency spreads to their respective phenyltropane analogues. Without as much of a discrepancy between the differing isomers of the piperidine class with respect to affinity and binding values as had in the phenyltropanes.

p-chloro & related (piperidine homologues of phenyltropanes)

Phenyltropane piperidine analogues^[1]

Structure	Compound # (S. Singh)	X = para- / 4′- Substitution	R = 2-tropane position	DAT (IC50 nM) [H3]WIN 35428 binding displacement	DA (IC50 nM) [H3]DA uptake	Selectivity Uptake/Binding
	Cocaine	H	CO2Me	102 ± 9	239 ± 1	2.3
	(±)-166a	Cl	β-CO2CH3	53.7 ± 1.9	37.8 ± 7.9	0.7
	(-)-166a	Cl	β-CO2CH3	24.8 ± 1.6	85.2 ± 2.6	3.4
	(+)-166a	Cl	β-CO2CH3	1360 ± 125	5090 ± 172	3.7
	(-)-167a	Cl	β-CO2OH	75.3 ± 6.2	49.0 ± 3.0	0.6
	(+)-167a	Cl	β-CO2OH	442 ± 32	—	—
	(-)-168a	Cl	β-CO2OAc	44.7 ± 10.5	62.9 ± 2.7	1.4
	(+)-168a	Cl	β-CO2OAc	928 ± 43	2023 ± 82	2.2
	(-)-169a[40]	Cl	β-n-Pr	3.0 ± 0.5	8.3 ± 0.6	2.8
	(-)-170a	H	β-CO2CH3	769 ± 19	—	—
	(±)-166b	Cl	α-CO2CH3	197 ± 8	—	—
	(+)-166b	Cl	α-CO2CH3	57.3 ± 8.1	34.6 ± 3.2	0.6
	(-)-166b	Cl	α-CO2CH3	653 ± 38	195 ± 8	0.3
	(+)-167b	Cl	α-CO2OH	240 ± 18	683 ± 47	2.8
	(+)-168b	Cl	α-CO2OAc	461 ± 11	—	—
	(+)-169b	Cl	α-n-Pr	17.2 ± 0.5	23.2 ± 2.2	1.3

naphthyl & related (piperidine homologues of phenyltropanes)

Activity @ MAT for piperidine homologues of phenyltropanes, including naphthyl derivatives^[41]

Structure	Compound #	[H3]DA uptake (nM) IC50	[H3]DA uptake (nM) Ki	[H3]NE uptake (nM) IC50	[H3]NE uptake (nM) Ki	[H3]5-HTT uptake (nM) IC50	[H3]5-HTT uptake (nM) Ki	Uptake Ratio DA/5-HT (Ki)	Uptake Ratio NE/5-HT (Ki)
	Cocaine	459 ± 159	423 ± 147	127 ± 4.1	108 ± 3.5	168 ± 0.4	155 ± 0.4	2.7	0.69
	Fluoxetine	>4500	>2500	193 ± 4.1	176 ± 3.5	8.1 ± 0.7	7.3 ± 0.7	624	24
	20	75 ± 9.1	69 ± 8.1	101 ± 3.3	88 ± 2.9	440 ± 30	391 ± 27	0.18	0.23
	6	23 ± 1.0	21 ± 0.9	-	34 ± 0.8	8.2 ± 0.3	7.6 ± 0.2	2.8	4.5
	7	>1000	947 ± 135	-	241 ± 1.7	8.2 ± 0.3	7.6 ± 0.2	22.6	5.7
	8	94 ± 9.6	87 ± 8.9	-	27 ± 1.6	209 ± 17	192 ± 16	0.45	0.14
	9	293 ± 6.4	271 ± 5.9	-	38 ± 4.0	13 ± 0.7	12 ± 0.7	23	3.2
	19	97 ± 8.6	90 ± 8.0	34 ± 2.5	30 ± 2.3	3.9 ± 0.5	3.5 ± 0.5	26	8.6
	10	326 ± 1.2	304 ± 1.1	337 ± 37	281 ± 30	113 ± 4.3	101 ± 3.8	3.0	2.8
	14	144 ± 20	131 ± 18	204 ± 5.6	175 ± 4.8	155 ± 3.9	138 ± 3.5	0.95	1.3
	15	>1800	>1700	>1300	>1100	275 ± 39	255 ± 37	>6	>4
	16	>1000	964 ± 100	>1200	>1000	334 ± 48	309 ± 44	3.1	3.5
	17	213 ± 30	187 ± 26	399 ± 12	364 ± 9.2	189 ± 37	175 ± 34	1.1	2.1
	18	184 ± 30	173 ± 26	239 ± 42	203 ± 36	67 ± 4.5	62 ± 4.1	2.8	3.3

distal-nitrogen 'dimethylamine' (piperidine-like cyclohexyl homologues of phenyltropanes)^[3]

cf. Fencamfamine

Radiolabeled

Radiolabel Tropane:^[42] Page 64. G.A. Whitlock et al. Table 1 Potential SRI PET and SPECT ligands.

Code	SERT Ki (nM)	NET Ki (nM)	DAT Ki (nM)	Radiolabel	In vivo study	Refs.
1	0.2	102.2	29.9	11C	Non-human primate	[43]
2	0.2	31.7	32.6	11C	Non-human primate	[44]
3	0.05	24	3.47	123I	Rat	[45]
4	0.08	28	13	18F	Non-human primate	[46]
5	0.11	450	22	11C	Rat, monkey	[47]

Transition metal complexes

These compounds include transition metals in their heteroatomic conformation, unlike non-radiolabel intended chelates where their element is chosen for intrinsic affectation to binding and function, these are tagged on by a "tail" (or similar) with a sufficient spacer to remain separated from known binding properties and instead are meant to add radioactivity enough to be easily tracked via observation methods that utilize radioactivity. As for anomalies of binding within the spectrum of the under-written kinds just mentioned: other factors not otherwise considered to account for its relatively lower potency, "compound 89c" is posited to protrude forward at the aryl place on its moiety toward the MAT ligand acceptor site in a manner detrimental to its efficacy. That is considered due to the steric bulk of the eight-position "tail" chelate substituted constituent, overreaching the means by which it was intended to be isolated from binding factors upon a tail, and ultimately nonetheless, interfering with its ability to bind. However, to broach this discrepancy, decreasing of the nitrogen tether at the eight position by a single methylene unit (89d) was shown to bring the potency of the analogous compound to the expected, substantially higher, potency: The N-methyl analog of 89c having an IC₅₀ of 1.09 ± 0.02 @ DAT & 2.47 ± 0.14 nM @ SERT; making 89c upwards of thirty-three times weaker at those MAT uptake sites.^{[lower-alpha 9]}

"Transition metal" chelated phenyltropanes^[1]

Structure	Compound # (S. Singh)	X = para- / 4′- Substitution	Configuration	DAT (IC50 nM) displacement of [H3]WIN 35428	5-HTT (IC50 nM) [H3]Citalopram	Selectivity 5-HTT/DAT
	WIN 35428	F	-	11.0 ± 1.0	160 ± 20	14.5
2β-chelated phenyltropanes
	73 TRODAT-1ɑ	Cl	-	R=13.9, S=8.42b	-	-
	74 TROTEC-1	F	-	high affinity site = 0.15 ± 0.04c low affinity site = 20.3 ± 16.1c	-	-
N-chelated phenyltropanes
	89a	F	2β	5.99 ± 0.81	124 ± 17	20.7
	89b	F	2α	2960 ± 157	5020 ± 1880	1.7
	89c	3,4-Cl2	2β	37.2 ± 3.4	264 ± 16	7.1
	89d	Cl	-	0.31 ± 0.03d	-	-

• ^ɑIUPAC: [2-[[2-[[[3-(4-chlorophenyl)-7-methyl-8-azabicyclo[3,2,1]oct-2-yl]methyl]-(2-mercaptoethyl)amino]ethyl]amino]ethanethiolato-(3—)-N2, N2′, S2, S2′]oxo-[1''R''-(''exo'', ''exo'')]-[99mTc]technetium
• ^bR- & S- isomer values are K_i (nM) for displacement of [¹²⁵I]IPT with technetium-99m replaced by rhenium
• ^cIC₅₀ (nM) values for displacement of [³H]WIN 35428 with ligand tricarbonyltechnetium replaced with rhenium. (IC₅₀ for WIN 35428 were 2.62 ± 1.06 @ high affinity binding & 139 ± 72 @ low affinity binding sites)
• ^dK_i value for displacement of [¹²⁵I]IPT radioligand.

Select annotations of above

Phenyltropanes can be grouped by "N substitution" "Stereochemistry" "2-substitution" & by the nature of the 3-phenyl group substituent X.
Often this has dramatic effects on selectivity, potency, and duration, also toxicity, since phenyltropanes are highly versatile. For more examples of interesting phenyltropanes, see some of the more recent patents, e.g. U.S. Patent 6,329,520, U.S. Patent 7,011,813, U.S. Patent 6,531,483, and U.S. Patent 7,291,737.

Potency in vitro should not be confused with the actual dosage, as pharmacokinetic factors can have a dramatic influence on what proportion of an administered dose actually gets to the target binding sites in the brain, and so a drug that is very potent at binding to the target may nevertheless have only moderate potency in vivo. For example, RTI-336 requires a higher dosage than cocaine. Accordingly, the active dosage of RTI-386 is exceedingly poor despite the relatively high ex vivo DAT binding affinity.

Sister substances

Many molecular drug structures have exceedingly similar pharmarcology to phenyltropanes, yet by certain technicalities do not fit the phenyltropane moniker. These are namely classes of dopaminergic cocaine analogues that are in the piperidine class (a category that includes methylphenidate) or benztropine class (such as Difluoropine: which is extremely close to fitting the criteria of being a phenyltropane.) Whereas other potent DRIs are far removed from being in the phenyltropane structural family, such as Benocyclidine or Vanoxerine.

See also

• List of cocaine analogues
  • List of local anesthetics
• List of methylphenidate analogues

References

Citations

Im-pact indices (exact locations within sources cited) & foot-notations

External links

• U. S. Provisional Patent Application listing examples of compounds that are tropanes for prospective use in research
• Article on cocaine analogue research