Novel 3alpha-diphenylmethoxytropane analogs: selective dopamine uptake inhibitors with behavioral effects distinct from those of cocaine

The pharmacological effects were assessed for a series of 3alpha-diphenylmethoxy-1alphaH,5alphaH-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 3alpha-(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 3alpha-(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 3alpha-(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 3alpha-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 3alpha-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 3alpha-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.