3'-Chloro-3α-(diphenylmethoxy)tropane but not 4'-chloro-3α- (diphenylmethoxy)tropane produces a cocaine-like behavioral profile

Richard H. Kline, Sari E Izenwasser, Jonathan L. Katz, David B. Joseph, Wayne D. Bowen, Amy Hauck Newman

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

A series of 2'- and 3'-substituted and 3',3''-disubstituted 3α- (diphenylmethoxy)tropane analogs were designed and synthesized as novel probes for the dopamine transporter. All the analogs were evaluated for displacement of [3H]WIN 35,428 binding at the dopamine transporter and for inhibition of [3H]dopamine uptake in rat caudate putamen. Compounds were observed to monophasically displace [3H]WIN 35,428 binding to the dopamine transporter with affinities of 21.6-1836 nM (K(i)). Generally, meta- substituted compounds were more potent than benztropine and equipotent to or slightly less potent than their previously reported parasubstituted homologs in inhibiting [3H]WIN 35,428 binding. However, these same metasubstituted analogs were typically less potent than the 4'-substituted analogs in inhibiting [3H]dopamine uptake. Ortho-substituted analogs were generally less potent in both binding and inhibition of uptake at the dopamine transporter than either benztropine or other aryl-substituted homologs. The analogs were also tested for binding at norepinephrine and serotonin transporters as well as muscarinic m1 receptors. None of the compounds in the present study bound with high affinity to either the norepinephrine or serotonin transporters, but all bound to muscarinic m1 receptors with high affinity (K(i) = 0.41-2.52 nM). Interestingly, 3'-chloro-3α- (diphenylmethoxy)tropane (5c) produced effects like cocaine in animals trained to discriminate 10 mg/kg cocaine from saline, unlike its 4'-Cl homolog and all of the previously evaluated benztropine analogs. Further evaluation of compound 5c and the other benztropine analogs will undoubtedly prove useful in the elucidation of the role of the dopamine transporter in the reinforcing effects of cocaine and the ultimate identification of a cocaine-abuse treatment.

Original languageEnglish
Pages (from-to)851-857
Number of pages7
JournalJournal of Medicinal Chemistry
Volume40
Issue number6
DOIs
StatePublished - Mar 14 1997
Externally publishedYes

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Dopamine Plasma Membrane Transport Proteins
Benztropine
Cocaine
Muscarinic M1 Receptors
Norepinephrine Plasma Membrane Transport Proteins
Serotonin Plasma Membrane Transport Proteins
Dopamine
Tropanes
Cocaine-Related Disorders
Putamen
Rats
Animals
3'-chloro-3-(diphenylmethoxy)tropane
4'-chloro-3-(diphenylmethoxy)tropane

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

3'-Chloro-3α-(diphenylmethoxy)tropane but not 4'-chloro-3α- (diphenylmethoxy)tropane produces a cocaine-like behavioral profile. / Kline, Richard H.; Izenwasser, Sari E; Katz, Jonathan L.; Joseph, David B.; Bowen, Wayne D.; Newman, Amy Hauck.

In: Journal of Medicinal Chemistry, Vol. 40, No. 6, 14.03.1997, p. 851-857.

Research output: Contribution to journalArticle

Kline, Richard H. ; Izenwasser, Sari E ; Katz, Jonathan L. ; Joseph, David B. ; Bowen, Wayne D. ; Newman, Amy Hauck. / 3'-Chloro-3α-(diphenylmethoxy)tropane but not 4'-chloro-3α- (diphenylmethoxy)tropane produces a cocaine-like behavioral profile. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 6. pp. 851-857.
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abstract = "A series of 2'- and 3'-substituted and 3',3''-disubstituted 3α- (diphenylmethoxy)tropane analogs were designed and synthesized as novel probes for the dopamine transporter. All the analogs were evaluated for displacement of [3H]WIN 35,428 binding at the dopamine transporter and for inhibition of [3H]dopamine uptake in rat caudate putamen. Compounds were observed to monophasically displace [3H]WIN 35,428 binding to the dopamine transporter with affinities of 21.6-1836 nM (K(i)). Generally, meta- substituted compounds were more potent than benztropine and equipotent to or slightly less potent than their previously reported parasubstituted homologs in inhibiting [3H]WIN 35,428 binding. However, these same metasubstituted analogs were typically less potent than the 4'-substituted analogs in inhibiting [3H]dopamine uptake. Ortho-substituted analogs were generally less potent in both binding and inhibition of uptake at the dopamine transporter than either benztropine or other aryl-substituted homologs. The analogs were also tested for binding at norepinephrine and serotonin transporters as well as muscarinic m1 receptors. None of the compounds in the present study bound with high affinity to either the norepinephrine or serotonin transporters, but all bound to muscarinic m1 receptors with high affinity (K(i) = 0.41-2.52 nM). Interestingly, 3'-chloro-3α- (diphenylmethoxy)tropane (5c) produced effects like cocaine in animals trained to discriminate 10 mg/kg cocaine from saline, unlike its 4'-Cl homolog and all of the previously evaluated benztropine analogs. Further evaluation of compound 5c and the other benztropine analogs will undoubtedly prove useful in the elucidation of the role of the dopamine transporter in the reinforcing effects of cocaine and the ultimate identification of a cocaine-abuse treatment.",
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