Interaction between a hydroxypiperidine analogue of 4-(2-benzhydryloxy-ethyl)-1-(4-fluorobenzyl)piperidine and Aspartate 68 in the human dopamine transporter.
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.
Zhen
Juan
J
Department of Biological Sciences, Illinois State University, Normal, IL 61790, USA.
Maiti
Soumen
S
Chen
Nianhang
N
Dutta
Aloke K
AK
Reith
Maarten E A
ME
D000818:Animals; D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism*; D001559:Benzhydryl Compounds / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000493:pharmacokinetics; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009638:Norepinephrine / Q000493:pharmacokinetics; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014316:Tritium
C499992:4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidine; D001559:Benzhydryl Compounds; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; D010880:Piperidines; D014316:Tritium; D001224:Aspartic Acid; D012701:Serotonin; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; C043425:vanoxerine; C044630:1-(2 (diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine; D003042:Cocaine; D004298:Dopamine; D009638:Norepinephrine