Dopamine transporter binding without cocaine-like behavioral effects: synthesis and evaluation of benztropine analogs alone and in combination with cocaine in rodents

Rationale: Previous SAR studies demonstrated that small halogen substitutio ns on the diphenylether system of benztropine (BZT), such as a para-Cl grou p, retained high affinity at the cocaine binding site on the dopamine trans porter Despite this high affinity, the compounds generally had behavioral e ffects different from those of cocaine. However, compounds with meta-Cl sub stitutions had effects more similar to those of cocaine. Objectives: A seri es of phenyl-ring analogs of benztropine (BZT) substituted with 3'-, 4'-, 3 ',4 "- and 4',4 " -position CI-groups were synthesized and their pharmacolo gy was evaluated in order to assess more fully the contributions to pharmac ological activity of substituents in these positions. Methods: Compounds we re synthesized and their pharmacological activity was assessed by examining radioligand binding and behavioral techniques. Results: All of the compoun ds displaced [H-3]WIN 35,428 binding with affinities ranging from 20 to 32. 5 nM. Affinities at norepinephrine ([H-3]nisoxetine) and serotonin ([H-3]ci talopram) transporters, respectively ranged from 259 to 5120 and 451 to 298 0 nM. Each of the compounds also inhibited [H-3]pirenzepine binding to musc arinic M-1 receptors, with affinities ranging from 0.98 to 47.9 nM. Cocaine and the BZT analogs produced dose-related increases in locomotor activity in mice. However, maximal effects of the BZT analogs were uniformly less th an those produced by cocaine, and were obtained 2-3 h after injection compa red to the relatively rapid onset (within 30 min) of cocaine effects. In ra ts trained to discriminate IP saline from 29 mu mol/kg cocaine (10 mg/kg), cocaine produced a dose-related increase in responding on the cocaine lever , reaching 100% at the training dose; however, none of the BZT analogs full y substituted for cocaine, with maximum cocaine responding from 20 to 69%. Despite their reduced efficacy compared to cocaine in cocaine discriminatio n, none of the analogs antagonized the effects of cocaine. As has been repo rted previously for 4'-Cl-BZT, the cocaine discriminative-stimulus effects were shifted leftward by co-administration of the present BZT analogs. Conc lusions: The present results indicate that although the BZT analogs bind wi th relatively high affinity and selectivity at the dopamine transporter, th eir behavioral profile is distinct from that of cocaine. The present result s suggest that analogs of BZT may be useful as treatments for cocaine abuse in situations in which an agonist treatment is indicated. These compounds possess features such as reduced efficacy compared to cocaine and a long du ration of action that may render them particularly useful leads for the dev elopment of therapeutics for cocaine abusers.