Structure-activity relationships at monoamine transporters and muscarinic receptors for N-substituted-3α-(3′-chloro-, 4′-chloro-, and 4′,4″-dichloro-substituted-diphenyl)methoxytropanes

A. H. Newman, M. J. Robarge, I. M. Howard, S. L. Wittkopp, C. George, T. Kopajtic, Sari E Izenwasser, J. L. Katz

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

The design, synthesis, and evaluation of 3α-(diphenylmethoxy)tropane (benztropine) analogues have provided potent and selective probes for the dopamine transporter. Structure-activity relationships (SARs) have been developed that contrast with those described for cocaine, despite significant structural similarity. Furthermore, behavioral evaluation of many of the benztropine analogues in animal models of cocaine abuse has suggested that these two classes of tropane-based dopamine uptake inhibitors have distinct pharmacological profiles. In general, the benztropine analogues do not demonstrate efficacious locomotor stimulation in mice, do not fully substitute for a cocaine discriminative stimulus, and are not appreciably self-administered in rhesus monkeys. These compounds are generally more potent than cocaine as dopamine uptake inhibitors in vitro, although their actions in vivo are not consistent with this action. These observations suggest that differing binding profiles at the serotonin and norepinephrine transporters as well as at muscarinic receptors might have significant impact on the pharmacological actions of these compounds. In addition, by varying the structures of the parent compounds and thereby modifying their physical properties, pharmacokinetics as well as pharmacodynamics will be directly affected. Therefore, in an attempt to systematically evaluate the impact of chemical modification on these actions, a series of N-substituted (H, CH3, allyl, benzyl, propylphenyl, and butylphenyl) analogues of 3′-chloro-, 4′-chloro-, and 4,4″-dichloro-3α-(diphenylmethoxy)tropanes were synthesized. These compounds were evaluated for displacement, in rat tissue, of [3H]WIN 35,428 from the dopamine transporter, [3H]citalopram from the serotonin transporter, [3H]nisoxetine from the norepinephrine transporter, and [3H]pirenzepine from muscarinic m1 receptors. SARs were developed and compared to a series of N-substituted-3α-(bis-4′-fluorophenyl)methoxytropanes. The present SARs followed previously reported studies with the single exception of the N-butylphenyl substituent, which did not provide the high affinity binding in any of these three sets of analogues, as it did in the 4′,4″ difluoro series. X-ray crystallographic analyses of the three parent ligands (1a, 2a, and 3a) were compared to that of 3α-(bis-4′-fluorophenyl)methoxytropane which provided supportive evidence toward the proposal that the combination of steric bulk in both the 3-position and the N-substituent, in this class of compounds, is not optimal for binding at the dopamine transporter. These studies provide binding profile data that can now be used to correlate with future behavioral analyses of these compounds and may provide insight into the kind of binding profile that might be targeted as a potential treatment for cocaine abuse.

Original languageEnglish
Pages (from-to)633-640
Number of pages8
JournalJournal of Medicinal Chemistry
Volume44
Issue number4
DOIs
StatePublished - Feb 15 2001

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Benztropine
Tropanes
Dopamine Plasma Membrane Transport Proteins
Muscarinic Receptors
Structure-Activity Relationship
Cocaine
Dopamine Uptake Inhibitors
Norepinephrine Plasma Membrane Transport Proteins
Cocaine-Related Disorders
Serotonin Plasma Membrane Transport Proteins
nisoxetine
Pharmacology
Muscarinic M1 Receptors
Pirenzepine
Citalopram
Macaca mulatta
Pharmacodynamics
Animal Models
Pharmacokinetics
X-Rays

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Structure-activity relationships at monoamine transporters and muscarinic receptors for N-substituted-3α-(3′-chloro-, 4′-chloro-, and 4′,4″-dichloro-substituted-diphenyl)methoxytropanes. / Newman, A. H.; Robarge, M. J.; Howard, I. M.; Wittkopp, S. L.; George, C.; Kopajtic, T.; Izenwasser, Sari E; Katz, J. L.

In: Journal of Medicinal Chemistry, Vol. 44, No. 4, 15.02.2001, p. 633-640.

Research output: Contribution to journalArticle

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AU - Newman, A. H.

AU - Robarge, M. J.

AU - Howard, I. M.

AU - Wittkopp, S. L.

AU - George, C.

AU - Kopajtic, T.

AU - Izenwasser, Sari E

AU - Katz, J. L.

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N2 - The design, synthesis, and evaluation of 3α-(diphenylmethoxy)tropane (benztropine) analogues have provided potent and selective probes for the dopamine transporter. Structure-activity relationships (SARs) have been developed that contrast with those described for cocaine, despite significant structural similarity. Furthermore, behavioral evaluation of many of the benztropine analogues in animal models of cocaine abuse has suggested that these two classes of tropane-based dopamine uptake inhibitors have distinct pharmacological profiles. In general, the benztropine analogues do not demonstrate efficacious locomotor stimulation in mice, do not fully substitute for a cocaine discriminative stimulus, and are not appreciably self-administered in rhesus monkeys. These compounds are generally more potent than cocaine as dopamine uptake inhibitors in vitro, although their actions in vivo are not consistent with this action. These observations suggest that differing binding profiles at the serotonin and norepinephrine transporters as well as at muscarinic receptors might have significant impact on the pharmacological actions of these compounds. In addition, by varying the structures of the parent compounds and thereby modifying their physical properties, pharmacokinetics as well as pharmacodynamics will be directly affected. Therefore, in an attempt to systematically evaluate the impact of chemical modification on these actions, a series of N-substituted (H, CH3, allyl, benzyl, propylphenyl, and butylphenyl) analogues of 3′-chloro-, 4′-chloro-, and 4,4″-dichloro-3α-(diphenylmethoxy)tropanes were synthesized. These compounds were evaluated for displacement, in rat tissue, of [3H]WIN 35,428 from the dopamine transporter, [3H]citalopram from the serotonin transporter, [3H]nisoxetine from the norepinephrine transporter, and [3H]pirenzepine from muscarinic m1 receptors. SARs were developed and compared to a series of N-substituted-3α-(bis-4′-fluorophenyl)methoxytropanes. The present SARs followed previously reported studies with the single exception of the N-butylphenyl substituent, which did not provide the high affinity binding in any of these three sets of analogues, as it did in the 4′,4″ difluoro series. X-ray crystallographic analyses of the three parent ligands (1a, 2a, and 3a) were compared to that of 3α-(bis-4′-fluorophenyl)methoxytropane which provided supportive evidence toward the proposal that the combination of steric bulk in both the 3-position and the N-substituent, in this class of compounds, is not optimal for binding at the dopamine transporter. These studies provide binding profile data that can now be used to correlate with future behavioral analyses of these compounds and may provide insight into the kind of binding profile that might be targeted as a potential treatment for cocaine abuse.

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