HOXY-3-(DIARYHNETHOXY)-1-ALPHA-H,5-ALPHA-H-TROPANE ANALOGS - SYNTHESIS AND INHIBITION OF BINDING AT THE DOPAMINE TRANSPORTER AND COMPARISONWITH PIPERAZINES OF THE GBR SERIES

We recently reported a new class of tropanes, based on benztropine, th at bind uniquely, in the S-configuration, to the dopamine transporter. We have now extended this series to evaluate the effects of substitue nts on the nitrogen and the diarylmethoxy group. Herein we have descri bed the synthesis and biological evaluation of a series of 2-carbometh oxy-3-( diarylmethoxy)-1 alpha H,5 alpha H-tropane (2-carbomethoxybenz tropine) analogs. Examination of the binding data obtained for these c ompounds shows that while the 4,4'-difluoro compound is potent and sel ective for the dopamine transporter, introduction of larger groups suc h as 4,4'-dichloro, 4,4'dibromo, 4,4'-diiodo, or 4,4'-dimethyl on the 3-diphenylmethoxy moiety reduces this potency. However, although intro duction of only one group (e.g., 4-chloro, 4-bromo, 4-iodo, or 4-methy l) leads to a similar reduction of binding affinity, these monosubstit uted 2-carbomethoxybenztropines are significantly more potent than the related disubstituted compounds. Finally, from the data for the N-sub stituted 2-carbomethoxybenztropine analogs, it is evident that steric bulk can be tolerated at the nitrogen site. A comparison of structure- activity relationship data for the tropanes, GBR analogs, and these be nztropines indicates that the 8-carbomethoxybenztropine analogs may be more like the GBR analogs in their mode of binding to the dopamine tr ansporter than like the tropanes. This conclusion supports the notion that the binding site for (-)-cocaine [and the (1R)-tropanes] may diff er from that of the 2-carbomethoxybenztropine analogs.