“List of phenyltropanes”的意思、由来-开放百科全书

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

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

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

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

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

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-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(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
Bn	CO₂Me	β,α	NMe	—	—	—	—	—

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	+	+++

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	—	—	—

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

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.^[5] (cf. the Dewar–Chatt–Duncanson model). In addition the planar dimension of the transition metal stacked arene becomes delocalized (cf. Bloom and Wheeler.^[29]).

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 (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.^[5]

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

Thiophenyltropanes

Diaryl

6/7-tropane position substituted

Displacement of Receptor-Bound [³H]WIN 35428 and Inhibition of [³H]DA Uptake by Transition Metal Complexes of 3β-Phenyltropanes^[5]
Structure	Compound # (S. Singh) Systematic name	K_i (nM)^ɑ	IC₅₀ (nM)	selectivity binding/uptake
21a^c	17 ± 15^b 224 ± 83	418	24.6
21b^d	2280 ± 183	3890	1.7
Cocaine	32 ± 5 388 ±221	405	12.6
Troparil (11a)	33 ± 17 314 ± 222	373	11.3

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

cf. the paroxetine homologue PTs

2β-carbmethoxy 6/7 substituted

3-butyl 6/7 substituted

intermediate 6- & 7-position synthesis modified phenyltropanes

8-tropane (bridgehead) position modified

6/7-Substituted 2-carbomethoxy-phenyltropanes^[5]
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	215^ɑ	-	-
104b	3β,2α, 6-OH 4′-Me	15310^ɑ	-	-
104c	3α,2β, 6-OH 4′-Me	930^ɑ	-	-
104d	3α,2α, 6-OH 4′-Me	7860^ɑ	-	-

6/7-Substituted 3-butyl-phenyltropanes^[5]
Structure	Compound # (S. Singh)	Substituent	K_i nM displacement of [H³]mazindol binding	K_i 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
121g	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
121m	7α-F	200 ± 10	680 ± 10	3.4
121n	7β-F	500 ± 10	550 ± 140	1.1

6/7-synthetic intermediates^[5]
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

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.^[33] 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.^[34]

Selected ββ Nortropanes
Code (S.S. #)	para {{smallsup>(unless position otherwise given inline)	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

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).^[35]

Paroxetine homologues

N-norphenyltropanes^[5]
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
75p^ɑ	3,4-Cl₂	0.66 ± 0.24	1.4^b	-	2.1	-

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

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 {{US patent|6150376}} {{Cite patent|WO|0007994}}

Bridged N-constrained phenyltropanes (fused/tethered)

See: Bridged cocaine derivatives & N8 Tricyclic (2β—crossed-over) N8—to—3β replaced aryl linked (expansive front-bridged) cocaine analogues

p-methyl aryl front & back N-bridged phenyltropanes

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.^[5]

3,4-Cl₂ aryl front-bridged phenyltropanes

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^[2]

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 (due to constraints in synthetic processes used in the creation of this compound) 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.^[38]

Cycloalkane-ring alterations of the tropane ring system

Azanonane (outer ring extended)

To better elucidate the binding requirements at MAT, the methylene unit on the tropane was extended by one to create the azanonane analogs.{{efn|^[5] ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#43 Page #967 (43rd page of article)] 2nd column}} 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.

Azabornane (outer ring contracted)

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.{{efn|^[5] ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#43 Page #967 (43rd page of article)] 2nd column}}

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.^[2]

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)

naphthyl & related (piperidine homologues of phenyltropanes)

distal-nitrogen 'dimethylamine' (piperidine-like cyclohexyl homologues of phenyltropanes)^[2]

Radiolabeled

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.{{efn|^[5] ←[https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf#31 Page #955 (31st page of article)] 1st (left) column, 2nd ¶}}

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. {{US Patent|6329520}}, {{US Patent|7011813}}, {{US Patent|6531483}}, and {{US Patent|7291737}}.

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

References

Citations

1. ^U.S. Patent Application Publication # US 2008/0153870 A1 M. J. Kuhar, et al. Jun. 26, 2008. Research Triangle Institute.
2. ^¹²³⁴⁵⁶⁷⁸⁹¹⁰{{US patent|6479509}}
3. ^¹²{{cite journal | doi = 10.1016/j.bmcl.2004.12.014 | title=Synthesis and monoamine transporter affinity of new 2β-carbomethoxy-3β-[4-(substituted thiophenyl)]phenyltropanes: discovery of a selective SERT antagonist with picomolar potency | journal=Bioorganic & Medicinal Chemistry| date=2005 | volume=15 | issue=4 | pages=1131–1133 | first=Gilles | last=Tamagnan | pmid=15686927}}
4. ^{{cite journal | date = Jul 2013 | title = Nonclassical Pharmacology of the Dopamine Transporter: Atypical Inhibitors, Allosteric Modulators, and Partial Substrates| journal = J Pharmacol Exp Ther | volume = 346 | issue = 1| pages = 2–10 Fig. 1 | doi = 10.1124/jpet.111.191056 | pmc=3684841 | pmid=23568856 | author1 = Schmitt| first1 = K. C.| last2 = Rothman| first2 = R. B.| last3 = Reith| first3 = M. E.}}
5. ^¹²³⁴⁵⁶⁷⁸⁹¹⁰¹¹¹²¹³¹⁴¹⁵¹⁶¹⁷¹⁸¹⁹²⁰²¹²²²³²⁴²⁵²⁶²⁷²⁸²⁹³⁰³¹{{Cite journal|url=https://www.erowid.org/archive/rhodium/pdf/cocaineanalogs.pdf|doi=10.1002/chin.200020238|title=Chem Inform Abstract: Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists|journal=ChemInform|volume=31|issue=20|pages=no|year=2000|last1=Singh|first1=Satendra}} [https://www.scribd.com/doc/77191354/Satendra-Singh-Chemistry-Design-and-Structure-Activity-Relationship-of-Cocaine-Antagonists Mirror hotlink.]
6. ^{{US patent|6479509}} Method of promoting smoking cessation.
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Im-pact indices (exact locations within sources cited) & foot-notations

External links

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Compound Structure	Short Name (S. Singh)	DAT [¹²⁵I]RTI-55 IC₅₀ (nM)	5-HTT [³H]Paroxetine K_i (nM)	NET [³H]Nisoxetine K_i (nM)	Selectivity 5-HTT/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

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
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

Structure	Compound # (S. Singh)	Para- (meta-)	DAT (IC₅₀ nM) displacement of [H³]WIN 35428	5-HTT (IC₅₀ nM) [H³]Citalopram
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

Structure	Compound # (S. Singh)	DAT (IC₅₀ nM) displacement of [H³]WIN 35428	5-HTT (IC₅₀ nM) [H³]Citalopram
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

Structure	Short Name (S. Singh)	Nitrogen side-chain (N8)	DAT [³H]GBR 12935 K_i (nM)	5-HTT [³H]Paroxetine K_i (nM)	NET [³H]Nisoxetine K_i (nM)	Selectivity 5-HTT/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	(CH₂)₃C₆H₅	1.4 ± 0.2^b	133 ± 7^c	-	95.0	-
82e	(CH₂)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	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
84s^d	CH₂CH=CH-CH₃	15 ± 1	75 ± 5	400 ± 80	5.0	26.7
84t^d	CH₂C(Br)=CH₂	30 ± 5	200 ± 40	>1000	6.7	-
84u^d	CH₂CH=CH₂I(E)	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-CH(CH₃)₂	500 ± 120	450 ± 80	>1000	0.9	-
85e^d	para-n-C₃H₇	500 ± 100	300 ± 12	750 ± 160	0.6	1.5

Structure	Compound	R₁	R₂	Inhibition of [³H]WIN 35,428 @ DAT IC₅₀ (nM)	Inhibition of [³H]Paroxetine @ 5-HTT K_i (nM)	Inhibition of [³H]Nisoxetine @ NET K_i (nM)	NET/DAT (uptake ratio)	NET/5-HTT (uptake ratio)
See 7a—7h table
	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

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/Coc-242	N8/2β-C(O)CH(CO2Me)CH2N para-chloro	—	7.67 ± 0.31^ɑ	226.54 ± 27.37^b	510.1 ± 51.4^c	—

Structure	Compound # (S. Singh)	K_i (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

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

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)
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

Code	SERT K_i (nM)	NET K_i (nM)	DAT K_i (nM)	Radiolabel	In vivo study	Refs.
1	0.2	102.2	29.9	¹¹C	Non-human primate	^[44]
2	0.2	31.7	32.6	¹¹C	Non-human primate	^[45]
3	0.05	24	3.47	¹²³I	Rat	^[46]
4	0.08	28	13	¹⁸F	Non-human primate	^[47]
5	0.11	450	22	¹¹C	Rat, monkey	^[48]

Structure	Compound # (S. Singh)	X = para- / 4′- Substitution	Configuration	DAT (IC₅₀ nM) displacement of [H³]WIN 35428	5-HTT (IC₅₀ nM) [H³]Citalopram
WIN 35428	F	-	11.0 ± 1.0	160 ± 20	14.5
2β-chelated phenyltropanes
73 TRODAT-1^ɑ	Cl	-	R=13.9, S=8.42^b	-	-
74 TROTEC-1	F	-	high affinity site = 0.15 ± 0.04^c low affinity site = 20.3 ± 16.1^c	-	-
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 ± 0.03^d	-	-

2-Carboxymethyl esters (phenyl-methylecgonines)

(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

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