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Research ArticleArticle

Novel 3α-Diphenylmethoxytropane Analogs: Selective Dopamine Uptake Inhibitors with Behavioral Effects Distinct from Those of Cocaine

Jonathan L. Katz, Sari Izenwasser, Richard H. Kline, Andrew C. Allen and Amy Hauck Newman
Journal of Pharmacology and Experimental Therapeutics January 1999, 288 (1) 302-315;
Jonathan L. Katz
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Sari Izenwasser
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Richard H. Kline
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Andrew C. Allen
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Amy Hauck Newman
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Abstract

The pharmacological effects were assessed for a series of 3α-diphenylmethoxy-1αH,5αH-tropane analogs which have structural similarities to cocaine. Like cocaine, these compounds displaced [3H]WIN 35,428 binding from rat caudate and had affinities ranging from approximately 10-fold greater than cocaine (Ki=11.8 nM) to relatively low affinity (Ki=2000 nM). The compounds also inhibited dopamine uptake with potencies corresponding to their affinities for WIN 35,428 binding sites. Like the parent compound, benztropine, the 3α-(diphenylmethoxy)tropane analogs displaced [3H]pirenzepine from muscarinic M1 receptors with affinities ranging from 2 to 120 nM. Cocaine produced dose-related increases in locomotor activity (horizontal ambulation) in Swiss Webster mice, whereas the 3α-(diphenylmethoxy)tropane analogs generally had lower efficacy than cocaine. Compounds with fluoro-substituents in the phenyl rings generally were among those with efficacy approaching that of cocaine; those with chloro- and bromo-substituents were markedly less efficacious, despite having binding affinities comparable to those of the corresponding fluoro-substituted compounds. The 3α-(diphenylmethoxy)tropane analogs were also examined in rats trained to discriminate saline from cocaine (10 mg/kg, i.p.). Cocaine produced a dose-related increase in responding on the cocaine-appropriate lever, reaching 100% at 10 mg/kg. Only the 4′,4"-difluoro-substituted analog produced effects similar to those of cocaine; the other compounds showed markedly reduced efficacy compared to cocaine. Drug interaction studies showed that the antimuscarinics, atropine and scopolamine, potentiated rather than attenuated the locomotor stimulant and cocaine-like discriminative-stimulus effects of cocaine, indicating that the antimuscarinic effects of the 3α-diphenylmethoxytropane analogs did not contribute to their diminished cocaine-like activity. Studies of the time course of selected compounds indicated that their reduced cocaine-like efficacy was likely not due to behavioral observations being conducted at an inopportune time period. Because none of the 3α-diphenylmethoxytropane analogs studied showed evidence that they were binding to more than one site, and because the structure activity relationships among these drugs are distinctly different from those obtained with cocaine, these data suggest that the 3α-diphenylmethoxytropane analogs are accessing a different binding domain than that accessed by cocaine. Binding to this domain may produce a behavioral profile that is distinct from that of the cocaine-like dopamine uptake inhibitors.

Footnotes

  • Send reprint requests to: Jonathan L. Katz, Psychobiology Section, National Institute on Drug Abuse Intramural Research Program, P.O. Box 5180, Baltimore, MD 21224. E-mail:jkatz{at}intra.nida.nih.gov

  • ↵1 Some of the locomotor activity data were provided through a contract (NO1DA-7–8076; M. J. Forester, PI) with the National Institute on Drug Abuse Medications Development Division. These studies were supported in part by an IntraAgency Agreement with the National Institute on Drug Abuse Medications Development Division and by the National Institute on Drug Abuse Intramural Research Program.

  • ↵2 Current address: Department of Neurology, University of Miami School of Medicine, 1501 NW 9th Ave., Room 4061, Miami, FL 33136.

  • ↵3 Current address: Medications Development Division, National Institute on Drug Abuse, National Institutes of Health, 5600 Fishers Lane, Room 11A-55, Rockville, MD 20857.

  • ↵4 Current address: Rhone-Poulenc Rorer, New Leads Discovery Section/Analytical Science, NMR S1362, 500 Arcola Road, H37, P.O. Box 5096, Collegeville, PA 19426-0800.

  • Abbreviations:
    BZT
    3α-(diphenylmethoxy)tropane (benztropine)
    4′
    4"-diF-BZT, 4′,4"-difluoro-3α-(diphenylmethoxy)tropane
    4′-Cl-BZT
    4′-chloro-3α-(diphenylmethoxy)tropane
    4′-Cl-BZT (β)
    4′-chloro-3β-(diphenylmethoxy)tropane
    ANOVA
    analysis of variance
    FR
    fixed ratio
    4′-Cl-BZT (β)
    4′-chloro-3β-(diphenylmethoxy)tropane
    4′
    4"-diBr-BZT, 4′,4"-dibromo-3α-(diphenylmethoxy)tropane
    • Received April 1, 1998.
    • Accepted August 21, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 1
1 Jan 1999
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Research ArticleArticle

Novel 3α-Diphenylmethoxytropane Analogs: Selective Dopamine Uptake Inhibitors with Behavioral Effects Distinct from Those of Cocaine

Jonathan L. Katz, Sari Izenwasser, Richard H. Kline, Andrew C. Allen and Amy Hauck Newman
Journal of Pharmacology and Experimental Therapeutics January 1, 1999, 288 (1) 302-315;

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Research ArticleArticle

Novel 3α-Diphenylmethoxytropane Analogs: Selective Dopamine Uptake Inhibitors with Behavioral Effects Distinct from Those of Cocaine

Jonathan L. Katz, Sari Izenwasser, Richard H. Kline, Andrew C. Allen and Amy Hauck Newman
Journal of Pharmacology and Experimental Therapeutics January 1, 1999, 288 (1) 302-315;
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