Abstract：
:Compound (+)-R,R-D-84 is an optically active trans-hydroxy-substituted derivative of 4-(2-benzhydryloxy-ethyl)-1-(4-fluorobenzyl)piperidine (D-164). As a hydroxypiperidine analog of GBR 12935, (+)-R,R-D-84 is a candidate dopamine transporter compound for the treatment of cocaine dependence. The present work addresses the functional activity of (+)-R,R-D-84 at monoamine transporters and its potential molecular mechanism involving acidic amino acids (D and E). The selectivity for the dopamine vs. serotonin transporter of (+)-R,R-D-84 was greater than that of (-)-S,S-D-83, its enantiomer, and the selectivity of both compounds was greater than that of GBR 12909 (diphenyl-fluorinated GBR 12935). Only (+)-R,R-D-84 displayed improved selectivity vs. the norepinephrine transporter. D313N or E215Q mutation did not alter the pattern of affinities (measured by membrane binding of the cocaine analog [3H]CFT) for the dopamine transporter of (+)-R,R-D-84, (-)-S,S-D-83, D-164 (non-hydroxylated analog), or GBR 12909. In contrast, D68N mutation specifically lowered the affinity of (+)-R,R-D-84, pointing to a role for D68 in the interaction with (+)-R,R-D-84, possibly through hydrogen bonding between the hydroxyl and the carboxyl group of D68 which is lacking in N68. The present results, combined with behavioral data, implicate D68 in the dopamine transporter in cocaine antagonist activity of (+)-R,R-D-84.
journal_name
Eur J Pharmacoljournal_title
European journal of pharmacologyauthors
Zhen J,Maiti S,Chen N,Dutta AK,Reith MEdoi
10.1016/j.ejphar.2004.10.028keywords:
subject
Has Abstractpub_date
2004-12-03 00:00:00pages
17-26issue
1eissn
0014-2999issn
1879-0712pii
S0014-2999(04)01198-7journal_volume
506pub_type
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