List of phenyltropanes

Phenyltropanes 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 that the cocaine benzoyloxy provided. The original purpose of which was to extirpate the cardiotoxicity inherent in the local anesthetic "numbing" capability of cocaine while retaining stimulant function. 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. Certain phenyltropanes can even be used as a smoking cessation aid. Many of the compounds were first elucidated in published material by the Research Triangle Institute and are thus named with "RTI" serial-numbers Similarly, a number of others are named for Sterling-Winthrop pharmaceuticals and Wake Forest University. The following includes many of the phenyltropane class of drugs that have been made and studied.
; which comprises a privileged scaffold of among the phenyltropane class of compounds.

2-Carboxymethyl esters (phenyl-methyl[ecgonine]s)

Like cocaine, phenyltropanes are considered a 'typical' or 'classical' 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 conformational state.
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. 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.
Blank spacings within tables for omitted data use "no data", "?", "-" or "—" interchangeably.

Structure	Short Name i.e. Trivial IUPAC Name	R of benzene	DA tritium\|WIN 35428 IC₅₀ nM	5HT paroxetine IC₅₀ nM	NE nisoxetine IC₅₀ nM	selectivity 5-HTT/DAT	selectivity NET/DAT
	cocaine	H	102 ± 12 241 ± 18^ɑ	1045 ± 89 112 ± 2^b	3298 ± 293 160 ± 15^c	10.2 0.5^d	32.3 0.7^e
	phenyltropane WIN 35,065-2 Troparil 11a	H	23 ± 5.0 49.8 ± 2.2^ɑ	1962 ± 61 173 ± 13^b	920 ± 73 37.2 ± 5.2^c	85.3 3.5^d	40.0 0.7^e
	para-fluorophenyltropane WIN 35,428 11b	F	14 22.9 ± 0.4^ɑ	156 100 ± 13^b	85 38.6 ± 9.9^c	51.6 4.4^d	53.2 1.7^e
	para-nitrophenyltropane 11k	NO₂	10.1 ± 0.10	?	?	?	?
	para-aminophenyltropane RTI-29 11j	NH₂	9.8 24.8 ± 1.3^g	5110	151	521.4	15.4
	para-chlorophenyltropane RTI-31 11c	Cl	1.12 ± 0.06 3.68 ± 0.09^ɑ	44.5 ± 1.3 5.00 ± 0.05^b	37 ± 2.1 5.86 ± 0.67^c	39.7 1.3^d	33.0 1.7^e
	para-methylphenyltropane RTI-32 Tolpane 11f	Me	1.71 ± 0.30 7.02 ± 0.30^ɑ	240 ± 27 19.38 ± 0.65^b	60 ± 0.53^e 8.42 ± 1.53^c	140 2.8^d	35.1 1.2^e
	para-bromophenyltropane RTI-51 Bromopane 11d	Br	1.81 ± 0.30	10.6 ± 0.24	37.4 ± 5.2	5.8	20.7
	para-iodophenyltropane RTI-55 Iometopane 11e	I	1.26 ± 0.04 1.96 ± 0.09^ɑ	4.21 ± 0.3 1.74 ± 0.23^b	36 ± 2.7 7.51 ± 0.82^c	3.3 0.9^d	28.6 3.8^e
	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	Sn₃	144 ± 37	—	—	—	—
	para-ethylphenyltropane RTI-83 11g	Et	55 ± 2.1	28.4 ± 3.8	4030 ± 381	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	CH₂	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-283^j 11u	CCH₃	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	2,800^k ± 300	0.5	186.6^k
	para--phenylethenylphenyltropane	cis-CH=CHPh	11.7 ± 1.12	—	—	—	—
	para-benzylphenyltropane	-CH₂-Ph	526 ± 65	7,240 ± 390	6670 ± 377	13.7	12.6
	para-phenylethenylphenyltropane	CH₂ ║ -C-Ph	474 ± 133	2,710 ± 800	7,060 ± 1,760	5.7	14.8
	para-phenylethylphenyltropane^l	-₂-Ph	5.14 ± 0.63	234 ± 26	10.8 ± 0.3	45.5	2.1
	para--phenylethenylphenyltropane^l RTI-436	trans–CH=CHPh	3.09 ± 0.75	335 ± 150	1960 ± 383	108.4	634.3
	para-phenylpropylphenyltropane^l	-₃-Ph	351 ± 52	1,243 ± 381	14,200 ± 1,800	3.5	40.4
	para-phenylpropenylphenyltropane^l	-CH=CH-CH₂-Ph	15.8 ± 1.31	781 ± 258	1,250 ± 100	49.4	79.1
	para-phenylbutylphenyltropane^l	-₄-Ph	228 ± 21	4,824 ± 170	2,310 ± 293	21.1	10.1
	para-phenylethynylphenyltropane^l RTI-298	–≡–Ph	3.7 ± 0.16	46.8 ± 5.8	347 ± 25	12.6	93.7
	para-phenylpropynylphenyltropane^l	–C≡C-CH₂Ph	1.82 ± 0.42	13.1 ± 1.7	27.4 ± 2.6	7.1	15
	para-phenylbutynylphenyltropane^l RTI-430	–C≡C₂Ph	6.28 ± 1.25	2180 ± 345	1470 ± 109	347.1	234
	para-phenylpentynylphenyltropane^l	–C≡C-₃-Ph	300 ± 37	1,340 ± 232	4,450 ± 637	4.46	14.8
	para-trimethylsilylethynylphenyltropane	—	—	—	—	—	—
	para-hydroxypropynylphenyltropane	—	—	—	—	—	—
	para-hydroxyhexynylphenyltropane^l	–C≡C-₄OH	57 ± 4	828 ± 29	9,500 ± 812	14.5	166.6
	para-phenyltropane Tamagnan	p-thiophene	12	0.017	189	0.001416	15.7
	para-biphenyltropane 11aa	Ph	10.3 ± 2.6^f 29.4 ± 3.8^ɑ 15.6 ± 0.6	95.8 ± 36	1,480 ± 269	6.1	94.8
	3β-2-naphthyltropane RTI-318 11bb	3β-2-naphthyl	0.51 ± 0.03 3.32 ± 0.08^f 3.53 ± 0.09^ɑ	0.80 ± 0.06	21.1 ± 1.0	1.5	41.3
	para-bimethoxyphenyltropane 15	OCH₂OCH₃^h	—	—	—	—	—

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

(3′,4′-Disubstituted phenyl)-tropanes

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

Compound	Short Name	R²	R¹	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 ± 0.08^ɑ	-	-	-	-
	meta-iodophenyltropane 16d	I	H	26.1 ± 1.7	-	-	-	-
	meta-tributylstannylphenyltropane 16e	SnBu₃	H	1100 ± 170	-	-	-	-
	meta-ethynylphenyltropane	C≡CH	H	-	-	-	-	-
	meta-methyl-para-fluorophenyltropane RTI-96 17a	CH₃	F	2.95 ± 0.58	-	-	-	-
	meta-methyl-para-chlorophenyltropane RTI-112^c 17b	CH₃	Cl	0.81 ± 0.05	10.5 ± 0.05	36.2 ± 1.0	13.0	44.7
	meta-para-dichlorophenyltropane RTI-111^b Dichloropane 17c	Cl	Cl	0.79 ± 0.08^b	3.13 ± 0.36^b	18.0 ± 0.8 17.96 ± 0.85^bd	4.0^b	22.8^b
	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
^cas ·HCl·2 H₂O
^dNE_N

Structure	Compound	R	X	_n	Inhibition of WIN 35,428 @ DAT IC₅₀	Inhibition of Paroxetine @ 5-HTT K_i	Inhibition of Nisoxetine @ NET K_i	NET/DAT	NET/5-HTT
	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	CH₂	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

Compound structure	Trivial IUPAC Name	R² ortho	R¹ para	DA	5HT	NE	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	ortho,para-dinitrophenyltropane	NO₂	NO₂	-	-	-	-	-

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

^ɑN=2

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

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

2-Carbmethoxy modified (replaced/substituted)

General 2-carbmethoxy modifications

2β-substitutions of ''p''-methoxy-phenyltropanes

^ɑN=2

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

^ɑKi value for displacement of DA uptake.
^bKi value for displacement of 5-HT uptake.
^cKi value for displacement of NE uptake.
^d5-HT uptake to DA uptake ratio.
^eNE uptake to 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	Me	-CO₂Ph	β,β	NMe	3.26	24,471	5,833
RTI-116	Cl	-CO₂	β,β	NMe	33	1,227	968
RTI-203	Cl	CO₂	β,β	NMe	9.37	2153	2744
RTI-204	Cl	-CO₂	β,β	NMe	3.91	3,772	4,783
RTI-205	Me	-CO₂	β,β	NMe	8.19	5,237	2,137
RTI-206	Cl	-CO₂	β,β	NMe	27.4	1,203	1,278

2-Phenyl-3-Phenyltropanes

Compound Structure	Short Name	Stereochemistry	X	DAT WIN 35428 IC₅₀	DAT Mazindol K_i	5-HTT Paroxetine IC₅₀	DA uptake K_i	5-HT uptake K_i	Selectivity 5-HT/DA
	Cocaine			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	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	-CO₂Pr^cyc	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	-CO₂Pr^cyc	β,β	NMe	0.96	168	235
RTI-193	Me	-CO₂Pr^cyc	β,β	NMe	1.68	1,066	644
RTI-117	Me	-CO₂Prⁱ	β,β	NMe	6.45	6,090	1,926
RTI-150	Me	-CO₂Bu^cyc	β,β	NMe	3.74	2,020	4,738
RTI-127	Me	-CO₂CEt₂	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)

Ethers (2-Alkyl)

See the N-desmethyl Paroxetine homologues

Molecular Structure	Short Name	Stereochemistry	DAT WIN 35428 IC₅₀	5-HTT Paroxetine IC₅₀	NET Nisoxetine IC₅₀	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

Structure	Code	X	2 Position	config	8	DA WIN 35428	NE nisoxetine	5-HT paroxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	RTI-106 27b	Cl	CONMe	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	CON₄	β,β	NMe	1.38 ± 0.03	3,950 ± 72	12400 ± 1207	8985	2862
	RTI-156	Cl	CON₅	β,β	NMe	6.61	5832	3468
	RTI-170	Cl	CONCH₂C≡CH	β,β	NMe	16.5	1839	4827
	RTI-172	Cl	CONNH₂	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	CONMe	β,β	NMe	0.85 ± 0.06	549 ± 18.5	724 ± 94	852	646
	RTI-186 29c	Me	CONMe	β,β	NMe	2.55 ± 0.43	422 ± 26	3402 ± 353	1334	165
	RTI-198 27h	Cl	CON₃	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	CONO₃	β,β	NMe	1.47 ± 0.13	1083 ± 76	2470 ± 56	1680	737
	RTI-214 27l	Cl	CON₂O	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	β,β	NMe	4.78	>30K	>16K
	RTI-218✲	Cl	CONOMe	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	CONO₃	β,β	NMe	0.75	446	230
	RTI-229 28a	I	CON₄	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 "CONMe" & "CONOMe" difference between methyl & methoxy render as the same.

Compound	Short Name	R	X	IC₅₀ DAT WIN 35428	IC₅₀ 5-HTT Paroxetine	IC₅₀ NET Nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	-	-	-	-	-	-	-	-
	29a	NH₂	CH₃	41.8 ± 2.45	6371 ± 374	4398 ± 271	152	105
	29b	N₂	CH₃	24.7 ± 1.93	33928 ± 2192	6222 ± 729	1374	252
	29c RTI-186	NCH₃	CH₃	2.55 ± 0.43	3402 ± 353	422 ± 26	1334	165
	29d RTI-222	4-morpholine	CH₃	11.7 ± 0.87	>100000	23601 ± 1156	>8547	2017

Carboxamide linked phenyltropanes dimers

Dimers of phenyltropanes, connected in their dual form using the C2 locant as altered toward a carboxamide structural configuring, as per Frank Ivy Carroll's patent inclusive of such chemical compounds, possibly so patented due to being actively delayed pro-drugs in vivo.

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 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 were employed with model compound 34. Focusing on the vicinity of the atoms @ positions A—C, the minima of electrostatic potential near atom position A, calculated with semi-empirical quantum mechanics computations found a correlation between affinity @ DAT and ΔV_min: wherein the values for the latter for 32c = 0, 32g = -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 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.

3-Substituted-isoxazol-5-yl

Code	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 32g	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-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	42,900
RTI-371	Me	p-chlorophenyl	8.74	>100K	>100K
RTI-386	Me	p-anisyl	3.93	756	4027
RTI-387	Me	p-fluorophenyl	6.45	917	>100K

3-Substituted-1,2,4-oxadiazole

Structure	Code	X	R	DAT displacement of WIN 35428	NET nisoxetine	5-HTT 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 '	Cl	3-methyl-1,2,4-oxadiazole	4.05 ± 0.57	363 ± 36	2584 ± 800	637	89.6
	ββRTI-126 '	H	3-methyl-1,2,4-oxadiazole	100 ± 6	7876 ± 551	3824 ± 420	38.3	788
	RTI-130 '	Cl	3-phenyl-1,2,4-oxadiazole	1.62 ± 0.02	245 ± 13	195 ± 5	120	151
	RTI-141 '	Cl	3--1,2,4-oxadiazole	1.81 ± 0.19	835 ± 8	337 ± 40	186	461
	RTI-143 '	Cl	3--1,2,4-oxadiazole	4.06 ± 0.22	40270 ± 180	404 ± 56	99.5	9919
	RTI-144 '	Cl	3--1,2,4-oxadiazole	3.44 ± 0.36	1825 ± 170	106 ± 10	30.8	532
	βRTI-151 '	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 '	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

Structure	Code	X	2 Group	DAT displacement of WIN 35428	NET displacement of nisoxetine	5-HTT displacement of 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	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		188.2 ± 5.01	595.25 ± 5738	5207 ± 488	316	28
	RTI-370	Me	3-isoxazol-5-yl	8.74	6980	>100K
	RTI-371	Cl	3-isoxazol-5-yl	13	>100K	>100K
	RTI-436	Me	-CH=CHPh	3.09	1960	335
	RTI-470	Cl	o-Cl-benzothiazol-2-yl	0.094	1590	1080
	RTI-451	Me	benzothiazol-2-yl	1.53	476	7120
	32g			1.28 ± 0.18	504 ± 29	2420 ± 136	1891	394
	32h			12.6 ± 10.3	929 ± 88	330 ± 196	262	73.7

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.

Acyl (C2-propanoyl)

2β-Acyl-3β-naphthyl substituted

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

^aK_i value for displacement of WIN 35428.

^bIC₅₀ value.

Irreversible covalent (''cf.'' ionic) C2 ligands

Irreversible binding ligand RTI-76: 4′-isothiocyanatophenyl -3--8-methyl-8-azabicyclooctane-2-carboxylate. Also known as: 3β-tropan-2β-carboxylic acid p-isothiocyanatophenylmethyl ester.

C2 Acyl, N8 phenylisothiocyanate

HD-205
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

Structure	Compound	R	X	Y	WIN 35,428 @ DAT K_i	Citalopram @ SERT K_i	Nisoxetine @ NET K_i	Pirenzepine @ M₁ K_i
	-	-	-	-	-	-	-	-
	9a	CH₃	H	H	34 ± 2	121 ± 19	684 ± 100	10,600 ± 1,100
	9b	F	H	H	49 ± 12	—	—	—
	9c	Cl	H	H	52 ± 2.1	147 ± 8	1,190 ± 72	11,000 ± 1,290
	9d	CH₃	Cl	H	80 ± 9	443 ± 60	4,400 ± 238	31,600 ± 4,300
	9e	F	Cl	H	112 ± 11	—	—	—
	9f	Cl	Cl	H	76 ± 7	462 ± 36	2,056 ± 236	39,900 ± 5,050
	9g	CH₃	F	F	62 ± 7	233 ± 24	1,830 ± 177	15,500 ± 1,400
	9h	F	F	F	63 ± 13	—	—	—
	9i	Cl	F	F	99 ± 18	245 ± 16	2,890 ± 222	16,300 ± 1,300
	-	-	-	-	-	-	-	-
	10a	CH₃	H	H	455 ± 36	530 ± 72	2,609 ± 195	12,600 ± 1,790
	10c	Cl	H	H	478 ± 72	408 ± 16	3,998 ± 256	11,500 ± 1,720
	10d	CH₃	Cl	H	937 ± 84	1,001 ± 109	22,500 ± 2,821	18,200 ± 2,600
	10f	Cl	Cl	H	553 ± 106	1,293 ± 40	5,600 ± 183	9,600 ± 600
	10g	CH₃	F	F	690 ± 76	786 ± 67	16,000 ± 637	9,700 ± 900
	10i	Cl	F	F	250 ± 40	724 ± 100	52,300 ± 13,600	9,930 ± 1,090
	-	-	-	-	-	-	-	-
	12a	H	H	H	139 ± 15	61 ± 9	207 ± 30	7,970 ± 631
	12b	H	Cl	H	261 ± 19	45 ± 3	—	24,600 ± 2,930
	12c	H	F	F	60 ± 7	—	—	—
	-	-	-	-	-	-	-	-
	-	-	-	-	-	-	-	-
	-	-	-	-	-	-	-	-

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

One patent claims a series of compounds with biotin-related sidechains are pesticides.

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

Structure	Code	para-X	C2-Tropane Position	config	DA	NE	5-HT
	—	H	F1	β,β	—	—	—
	RTI-224	Me	F1^c	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
	—	—	F3	β,β	—	—	—
	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	—
	—	—	F5	β,β	—	—	—
	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

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

Structure	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

Test Compound	DA uptake IC₅₀	NE uptake IC₅₀	5-HT uptake IC₅₀
-3--8-methyl-8-azabicyclooct-2-ene	0.079	0.026	0.0047

Test Compound	DA uptake IC₅₀	NE uptake IC₅₀	5-HT uptake IC₅₀
-3--8-methyl-8-azabicyclooct-2-ene	18	4.9	0.047
-3--8-methyl-8-azabicyclooct-2-ene	1.5	0.5	0.016
-3--8-methyl-8-azabicyclooct-2-ene	22.00	8.00	0.0036

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

β,α Stereochemistry

Structure	Compound '	X	2 Group	config	8	DAT IC₅₀ WIN 35428	5-HTT IC₅₀ paroxetine	NET IC₅₀ 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-352^ɑ *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-319^b	3α-2-naphthyl	CO₂Me	β,α	NMe	1.1 ± 0.09	11.4 ± 1.3	70.2 ± 6.28	—	—
	RTI-286^c 20b	F	CO₂Me	β,α	NMe	21 ± 0.57	5062 ± 485	1231 ± 91	241	58.6
	RTI-274^d	F	CH₂O	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
		Bn	CO₂Me	β,α	NMe	—	—	—	—	—

^ɑbcd'''

α,β Stereochemistry

Compound	DA	M.E.D.	Dose	Activity	Activity
-2--8-methyl-3--8-azabicyclooctane	0.39	<1	50	0	0
-2--8-methyl-3--8-azabicyclooctane	0.1	1	25	0	0
-2--8-methyl-3--8-azabicyclooctane	0.016	0.25	50	+	+++

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

fumaric acid salts (of α,β configured phenyltropanes)

Test Compound	DA uptake IC₅₀	NE uptake IC₅₀	5-HT uptake IC₅₀
-2--8-methyl-3--8-azabicyclooctane fumaric acid salt	0.062	0.035	0.00072
-2--8-methyl-3--8-azabicyclooctane fumaric acid salt	0.062	0.15	0.0063
-2--8-H-3--8-azabicyclooctane fumaric acid salt	0.10	0.048	0.0062
-2--8-H-3--8-azabicyclooctane fumaric acid salt	0.088	0.051	0.013

Arene equivalent alterations

''η''⁶-3β-(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.. In addition the planar dimension of the transition metal stacked arene becomes delocalized.
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. Attesting these as true examples relating useful effective applications for bioorganometallic chemistry.
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 is θ=131° for Cr₃ whereas Cp*Ru was θ=187° or only 30% larger. The tricarbonyl moiety being considered equivalent to the cyclopenta dienyl ligand.

^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: tricarbonylchromium
^dIUPAC: -ruthenium- triflate
3-(2-thiophene) and 3-(2-furan)

Code	Compound	DA	NE	5-HT
1	-2--8-methyl-3--8-aza-bicyclooctanefumaric acid salt	0.30	0.0019	0.00052
2	-2--8-methyl-3--8-aza-bicyclo-octane fumaric acid salt	0.36	0.0036	0.00042
3	-2--8-methyl-3--8-aza-bicyclo-octane fumaric acid salt	0.31	0.00090	0.00036
4	-2--8-methyl-3--8-aza-bicyclo-octane fumaric acid salt	0.92	0.0030	0.00053
5	-2--8-H-3--8-aza-bicyclooctane fumaric acid salt	0.074	0.0018	0.00074
6	-2--8-H-3--8-aza-bicyclooctane fumaric acid salt	0.19	0.0016	0.00054

Thiophenyltropanes

Diaryl

6/7-tropane position substituted

2β-carbomethoxy 6/7 substituted

^ɑIC₅₀ value for displacement of mazindol. IC₅₀ for cocaine 288 nM for displacement of mazindol
3-butyl 6/7 substituted

intermediate 6- & 7-position synthesis modified phenyltropanes

8-tropane (bridgehead) position modified

Nortropanes (''N''-demethylated)

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. 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.

Code '	X para	DA	5HT	NE
RTI-142 75b	F	4.39	68.6	18.8
RTI-98 75d Nor^ɑ-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 Nor^ɑ-RTI-280	para-Me meta-I	5.98 ± 0.48	1.06 ± 0.10	74.3 ± 3.8
RTI-305 Nor^ɑ-RTI-360/11y	Ethynyl	1.24 ± 0.11	1.59 ± 0.2	21.8 ± 1.0
RTI-307 Nor^ɑ-RTI-281/11z	Propynyl	6.11 ± 0.67	3.16 ± 0.33	115.6 ± 5.1
RTI-309 Nor^ɑ-11t	Vinyl	1.73 ± 0.05	2.25 ± 0.17	14.9 ± 1.18
RTI-330 Nor^ɑ-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
N-Me compound code#
→
N-demethylated derivative
compound code # para-X Paroxetine WIN 35,428 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

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".
Structure Short Name
Para-X DAT
WIN 35428 IC₅₀ 5-HTT
Paroxetine IC₅₀ NET
Nisoxetine IC₅₀ 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-CO₂CH₂ 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 CH₂ 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
75p^ɑ 3,4-Cl₂ 0.66 ± 0.24 1.4^b - 2.1 -

ɑThese values determined in Cynomolgus monkey caudate-putamen
b'The radioligand used for 5-HTT was citalopram
Compound Structure Short Name
DAT
RTI-55 IC₅₀ 5-HTT
Paroxetine K_i NET
Nisoxetine K_i'' 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
See the N-methyl paroxetine homologues
cf. [|di-aryl phenyltropanes] for another SSRI approximated hybrid: the fluoxetine based homologue of the phenyltropane class.
Compound Structure Short Name
Stereochemistry DAT
WIN 35428 IC₅₀ 5-HTT
Paroxetine IC₅₀ NET
Nisoxetine IC₅₀ 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.
8-oxa bridgehead replacements
8-carba bridgehead replacements
''N''-alkyl
Bi- and tri-cyclic aza compounds and their uses
Structure Short Name
Nitrogen side-chain
DAT
GBR 12935 K_i 5-HTT
Paroxetine K_i NET
Nisoxetine K_i 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 ± 2.9^ɑ - - - -
82b CH₂CH₂CH₃ 43.0 ± 17.7^ɑ - - - -
82c CH₂C₆H₅ 58.9 ± 1.65^b 1073^c - 18.2 -
82d ₃C₆H₅ 1.4 ± 0.2^b 133 ± 7^c - 95.0 -
82e ₅C₆H₅ 3.4 ± 0.83^b 49.9 ± 10.2^c - 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 CH₂CH₂₂ 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 CH₂CON₂ 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 COCH₂ 2100 ± 140 102 ± 23 >10000 0.05 -
84n ₂Pht 4.23 ± 0.48 0.84 ± 0.02 441 ± 66.0 0.2 104
84o ₃Pht 9.10 ± 1.10 0.59 ± 0.07 74.0 ± 11.6 0.06 8.1
84p ₄Pht 2.38 ± 0.22 0.21 ± 0.02 190 ± 18.0 0.09 79.8
84q ₅Pht 2.40 ± 0.17 0.34 ± 0.03 60.0 ± 3.10 0.1 25.0
84r ₈Pht 2.98 ± 0.30 0.20 ± 0.02 75.0 ± 3.6 0.07 25.2
84s^d CH₂CH=CH-CH₃ 15 ± 1 75 ± 5 400 ± 80 5.0 26.7
84t^d CH₂C=CH₂ 30 ± 5 200 ± 40 >1000 6.7 -
84u^d CH₂CH=CH₂I 30 ± 5 960 ± 60 295 ± 33 32.0 9.8
84v^d CH₂C≡CH 14 ± 1 100 ± 30 >1000 7.1 -
84w^d CH₂C₆H₅ 42 ± 12 100 ± 17 600 ± 100 2.4 14.3
84x^d CH₂C₆H₄-2-CH₃ 93 ± 19 225 ± 40 >1000 2.4 -
85a^d para-H 113 ± 41 100 ± 20 >1000 0.9 -
85b^d para-Cl, meta-Cl 29 ± 4 50 ± 6 500 ± 120 1.7 17.2
85c^d para-Me 17 ± 7 500 ± 30 >1000 29.4 -
85d^d para-CH₂ 500 ± 120 450 ± 80 >1000 0.9 -
85e^d para-n-C₃H₇ 500 ± 100 300 ± 12 750 ± 160 0.6 1.5

^ɑIC₅₀ for displacement of cocaine. IC₅₀ for cocaine = 67.8 ± 8.7
^bIC₅₀ values for displacement of WIN 35428
^cIC₅₀ values for displacement of citalopram
^dThe standard K_i value for the displacement of GBR 12935, paroxetine, and nisoxetine were 27 ± 2, 3 ± 0.2, and 80 ± 28 nM, respectively, for these experiments
Structure Compound R₁ R₂ Inhibition of WIN 35,428
@ DAT
IC₅₀ Inhibition of Paroxetine
@ 5-HTT
K_i Inhibition of Nisoxetine
@ NET
K_i NET/DAT
NET/5-HTT
See 7a—7h table - - - - - - - -
See 7a—7h table 7a CH₃ CH₃ 9 ± 3 0.7 ± 0.2 220 ± 10 24 314
See 7a—7h table 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
Bridged ''N''-constrained phenyltropanes (fused/tethered)
See: Bridged cocaine derivatives & N8 Tricyclic N8—to—3β replaced aryl linked cocaine analogues
''p''-methyl aryl front & back ''N''-bridged phenyltropanes
Compound #
2β=R Mazindol binding DA uptake 5-HT uptake NE uptake selectivity
5-HT/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/Coc-242 N8/2β-CCHCH2N
para-chloro — 7.67 ± 0.31^ɑ 226.54 ± 27.37^b 510.1 ± 51.4^c —

^ɑValue for displacement of WIN 35,428 binding @ DAT
^bValue for displacement of paroxetine binding to SERT
^cValue for displacement of 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 having 1.6—78× increased activity. -128 additionally exhibited 100× greater potency @ SERT, whereas 132a & 133a had 4—5.2× weaker 5-HTT activity. Front-bridged had a better 5-HT/DA reuptake ratio in favor of SERT, while the back-bridged preferred placement with DAT interaction.
3,4-Cl₂ aryl front-bridged phenyltropanes
Code Compound DA NE 5-HT
1 -2--8-azatricyclo- undecan-11 -one O-methyl-oxime 0.012 0.0020 0.0033
2 -2--8-azatricyclo- undecan-11-one 0.18 0.035 0.0075
3 -3--7-azatricyclo- decan-5-one O-methyl-oxime 0.0160 0.0009 0.0032
4 -2--8-azatricyclo- undecan-11-ol 0.0750 0.0041 0.0028
5 -3--7-azatricyclo- decan-5-one 0.12 0.0052 0.0026
6 -3--7-azatricyclo-decan-5-ol 0.25 0.0074 0.0018
7 -3- -7-azatricyclodec- 5-yl acetate 0.21 0.0061 0.0075
8 -3--5-methoxy-7- azatricyclodecane 0.022 0.0014 0.0001

1-Chloroethyl chloroformate is used to remove N-methyl of trans-aryltropanes.
2° amine is reacted with BrnCO₂Et.
Base used to abstract proton α- to CO₂Et group and complete the tricyclic ring closure step.
To make a different type of analog
Remove N-Me
Add ɣ-bromo-chloropropane
Allow for cyclization with K₂CO₃ base and KI cat.
C2 + C3 (side-chain) fused (carboxylate & benzene conjoined)
-15-methyl-15-azatetracyclopentadeca-4,5,7-trien-3-one
C3 to 1′ + 2′ (''ortho'') tropane locant dual arene bridged
Parent compound of a series of spirocyclic cocaine benzoyl linkage modification analogs created by Suzuki coupling method of ortho-substituted arylboronic acids and an enol-triflate derived from cocaine; which technically has the three methylene length of cocaine analogues as well as the single length which defines the phenyltropane series. Note that the carbomethoxyl group is alpha configured; which is not the usual, most prevalent, conformation favored for the PT cocaine-receptor binding pocket of most such sub-type of chemicals. The above and below depictions show attested compounds synthesized, additionally with variations upon the Endo–exo isomerism of their structures.
Cycloalkane-ring alterations of the tropane ring system
Azanonane (outer ring extended)
3-Phenyl-9-azabicyclononane derivatives
To better elucidate the binding requirements at MAT, the methylene unit on the tropane was extended by one to create the azanonane analogs. 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 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.
Structure Compound #
K_i
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-azabicycloheptane 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.. However piperidine homologues had comparable potencies.
File:2-exo-phenyl-7-azabicycloheptane.png|thumb|2-exo-phenyl-7-azabicycloheptane:

The non-carboxylic variant of exo-2-phenyl-7-azabicycloheptane-1-carboxylic acid

With the carboxy ester function removed the resultant derived compound acts as a DAT substrate drug, thus an amphetaminergic releaser of MAT & VMAT, yet similar to phenyltropanes cf. EXP-561 & BTQ.
Azabornanes with longer substitutions at the 3β-position or with the nitrogen in the position it would be on the piperidine homologues, 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.
Structure Compound #
K_i
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">Homology (chemistry)">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)
Heterocyclic N-Desmethyl
naphthyl & related (piperidine homologues of phenyltropanes)
distal-nitrogen 'dimethylamine' (piperidine-like cyclohexyl homologues of phenyltropanes)
cf. Fencamfamine
Radiolabeled
Code SERT K_i NET K_i DAT K_i Radiolabel In vivo study Refs.
1 0.2 102.2 29.9 ¹¹C Non-human primate
2 0.2 31.7 32.6 ¹¹C Non-human primate
3 0.05 24 3.47 ¹²³I Rat
4 0.08 28 13 ¹⁸F Non-human primate
5 0.11 450 22 ¹¹C Rat, monkey

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" 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 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.
^ɑIUPAC: oct-2-yl]methyl]-amino]ethyl]amino]ethanethiolato--N2, N2′, S2, S2′]oxo--technetium
^bR- & S- isomer values are K_i for displacement of IPT with technetium-99m replaced by rhenium
^cIC₅₀ values for displacement of WIN 35428 with ligand tricarbonyltechnetium replaced with rhenium.
^dK_i value for displacement of 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.,,, and.
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 or benztropine class Whereas other potent DRIs are far removed from being in the phenyltropane structural family, such as Benocyclidine or Vanoxerine.

See: List of cocaine analogues
Most any variant with a tropane locant—3-β connecting linkage differing from, e.g. longer than, a single methylene unit, including alkylphenyls is more correctly a "cocaine analogue" proper, and not a phenyltropane. Especially if this linkage imparts a sodium channel blocker functionality to the molecule:
More cocaine analogue examples

Citations
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List of phenyltropanes

2-Carboxymethyl esters (phenyl-methyl[ecgonine]s)

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

(3′,4′-Disubstituted phenyl)-tropanes

(2′,4′-Disubstituted phenyl)-tropanes

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

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

2-Carbmethoxy modified (replaced/substituted)

General 2-carbmethoxy modifications

2β-substitutions of ''p''-methoxy-phenyltropanes

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

Carboxyaryl

2-Phenyl-3-Phenyltropanes

Carboxyalkyl

2-Alkyl Esters & Ethers

Esters (2-Alkyl)

Ethers (2-Alkyl)

Carboxamides

Carboxamide linked phenyltropanes dimers

Heterocycles

3-Substituted-isoxazol-5-yl

3-Substituted-1,2,4-oxadiazole

Acyl (C2-propanoyl)

2β-Acyl-3β-naphthyl substituted

Ester reduction

2-Alkane/Alkene

Irreversible covalent (''cf.'' ionic) C2 ligands

C2 Acyl, N8 phenylisothiocyanate

Benztropine based (C2-position hetero-substituted) phenyltropanes

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

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

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

Aryl-Tropenes

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

β,α Stereochemistry

α,β Stereochemistry

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

fumaric acid salts (of α,β configured phenyltropanes)

Arene equivalent alterations

''η''6-3β-(transition metal complexed phenyl)tropanes

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

Thiophenyltropanes

Diaryl

6/7-tropane position substituted

2β-carbomethoxy 6/7 substituted

3-butyl 6/7 substituted

intermediate 6- & 7-position synthesis modified phenyltropanes

8-tropane (bridgehead) position modified

Nortropanes (''N''-demethylated)

Paroxetine homologues

''N''-replaced (S,O,C)

8-oxa bridgehead replacements

8-carba bridgehead replacements

''N''-alkyl

Bridged ''N''-constrained phenyltropanes (fused/tethered)

''p''-methyl aryl front & back ''N''-bridged phenyltropanes

3,4-Cl2 aryl front-bridged phenyltropanes

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

C3 to 1′ + 2′ (''ortho'') tropane locant dual arene bridged

Cycloalkane-ring alterations of the tropane ring system

Azanonane (outer ring extended)

Azabornane (outer ring contracted)

Piperidine homologues">Homology (chemistry)">homologues (inner two-carbon bridge excised)

''p''-chloro & related (piperidine homologues of phenyltropanes)

naphthyl & related (piperidine homologues of phenyltropanes)

distal-nitrogen 'dimethylamine' (piperidine-like cyclohexyl homologues of phenyltropanes)

Radiolabeled

Transition metal complexes

Select annotations of above

Sister substances

Citations

Im-pact">Citation impact">Im-pact indices">Citation index">indices (exact locations within sources cited) & foot-notations">Page footer">foot-notations

''η''⁶-3β-(transition metal complexed phenyl)tropanes

3,4-Cl₂ aryl front-bridged phenyltropanes