3'-CHLORO-3-ALPHA-(DIPHENYLMETHOXY)TROPANE BUT NOT 4'-CHLORO-3-ALPHA-(DIPHENYLMETHOXY)TROPANE PRODUCES A COCAINE-LIKE BEHAVIORAL PROFILE

A series of 2'- and 3'-substituted and 3',3''-disubstituted 3 alpha-(d iphenylmethoxy)tropane analogs were designed and synthesized as novel probes for the dopamine transporter. All the analogs were evaluated fo r displacement of [H-3]WIN 35,428 binding at the dopamine transporter and for inhibition of [H-3]dopamine uptake in rat caudate putamen. Com pounds were observed to monophasically displace [H-3]WIN 35,428 bindin g to the dopamine transporter with affinities of 21.6-1836 nM (K-i). G enerally, meta-substituted compounds were more potent than benztropine and equipotent to or slightly less potent than their previously repor ted para-substituted homologs in inhibiting [H-3]WIN 35,428 binding. H owever, these same meta-substituted analogs were typically less potent than the 4'-substituted analogs in inhibiting [H-3]dopamine uptake. O rtho-substituted analogs were generally less potent in both binding an d inhibition of uptake at the dopamine transporter than either benztro pine or other aryl-substituted homologs. The analogs were also tested for binding at norepinephrine and serotonin transporters as well as mu scarinic m(1) receptors. None of the compounds in the present study bo und with high affinity to either the norepinephrine or serotonin trans porters, but all bound to muscarinic m(1) receptors with high affinity (K-i = 0.41-2.52 nM). Interestingly, 3'-chloro-3 alpha-(diphenylmetho xy)tropane (5c) produced effects like cocaine in animals trained to di scriminate 10 mg/kg cocaine from saline, unlike its 4'-Cl homolog and all of the previously evaluated benztropine analogs. Further evaluatio n of compound 5c and the other benztropine analogs will undoubtedly pr ove useful in the elucidation of the role of the dopamine transporter in the reinforcing effects of cocaine and the ultimate identification of a cocaine-abuse treatment.