Dual DAT/sigma1 receptor ligands based on 3-(4-(3-(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-1-phenylpropan-1-ol.
Ester analogs of (+/-)3-(4-(3-(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-1-phenylpropan-1-ol were synthesized and evaluated for binding at DAT, SERT, NET, and sigma1 receptors, and compared to GBR 12909 and several known sigma1 receptor ligands. Most of these compounds demonstrated high affinity (K(i)=4.3-51 nM) and selectivity for the DAT among the monoamine transporters. S- and R-1-(4-(3-(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-3-phenylpropan-2-ol were also prepared wherein modest enantioselectivity was demonstrated at the DAT. However, no enantioselectivity at sigma1 receptors was observed and most of the ester analogs of the more active S-enantiomer showed comparable binding affinities at both DAT and sigma1 receptors with a maximal 16-fold DAT/sigma1 selectivity.
Cao
Jianjing
J
Medicinal Chemistry Section, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, USA.
Kopajtic
Theresa
T
Katz
Jonathan L
JL
Newman
Amy Hauck
AH
D000818:Animals; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C532461:3-(4-(3-(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-1-phenylpropan-1-ol; D002227:Carbazoles; D050483:Dopamine Plasma Membrane Transport Proteins; D010879:Piperazines; D017480:Receptors, sigma; C043425:vanoxerine; C034931:rimcazole; D003042:Cocaine
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