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Vol. 288, Issue 1, 302-315, January 1999
-Diphenylmethoxytropane Analogs: Selective Dopamine
Uptake Inhibitors with Behavioral Effects Distinct from Those of
Cocaine1
Psychobiology Section, National Institute on Drug Abuse, Intramural
Research Program, National Institutes of Health, Baltimore, Maryland
The pharmacological effects were assessed for a series of
3
-diphenylmethoxy-1H,5H-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
3-(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 3-(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 3-(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 3-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
3-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
3-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.
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