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

The pharmacological effects were assessed for a series of 3 alpha-diphenylm ethoxy-1 alpha H,5 alpha H-tropane analogs which have structural similariti es to cocaine. Like cocaine, these compounds displaced [H-3]WIN 35,428 bind ing from rat caudate and had affinities ranging from approximately 10-fold greater than cocaine (K-i = 11.8 nM) to relatively low affinity (K-i = 2000 nM). The compounds also inhibited dopamine uptake with potencies correspon ding to their affinities for WIN 35,428 binding sites. Like the parent comp ound, benztropine, the 3 alpha-(diphenylmethoxy)tropane analogs displaced [ H-3]pirenzepine from muscarinic M-1 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 alpha-(dipheny lmethoxy)tropane analogs generally had lower efficacy than cocaine. Compoun ds with fluoro-substituents in the phenyl rings generally were among those with efficacy approaching that of cocaine; those with chloro- and bromo-sub stituents were markedly less efficacious, despite having binding affinities comparable to those of the corresponding fluoro-substituted compounds. The 3 alpha-(diphenylmethoxy)tropane analogs were also examined in rats traine d to discriminate saline from cocaine (10 mg/kg, i.p.). Cocaine produced a dose-related increase in responding on the cocaine-appropriate lever, reach ing 100% at 10 mg/kg, Only the 4',4 "-difluoro-substituted analog produced effects similar to those of cocaine; the other compounds showed markedly re duced efficacy compared to cocaine. Drug interaction studies showed that th e antimuscarinics, atropine and scopolamine, potentiated rather than attenu ated the locomotor stimulant and cocaine-like discriminative-stimulus effec ts of cocaine, indicating that the antimuscarinic effects of the 3 alpha-di phenylmethoxytropane 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 o bservations being conducted at an inopportune time period. Because none of the 3 alpha-diphenylmethoxytropane analogs studied showed evidence that the y were binding to more than one site, and because the structure activity re lationships among these drugs are distinctly different from those obtained with cocaine, these data suggest that the 3 alpha-diphenylmethoxytropane an alogs are accessing a different binding domain than that accessed by cocain e. Binding to this domain may produce a behavioral profile that is distinct from that of the cocaine-like dopamine uptake inhibitors.