| Abstract
| - To explore structure−activity relationships (SAR) of a novel conformationally constrained leadcis-3,6-disubstituted piperidine derivative derived from (2,2-diphenylethyl)-[1-(4-fluorobenzyl)piperidine-4-ylmethyl]amine (I), a series of compounds was synthesized by derivatizing theexocyclic N-atom at the 3-position of the lead. This study led to the formation of substitutedphenyl and heterocyclic derivatives. All novel compounds were tested for their affinity at thedopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter(NET) in the brain by measuring their potency in competing for the binding of [3H]WIN 35428, [3H]citalopram, and [3H]nisoxetine, respectively. Selected compounds were also evaluatedfor their activity in inhibiting the uptake of [3H]DA. The SAR results demonstrated that thenature of substitutions on the phenyl ring is important in activity at the DAT with the presenceof an electron-withdrawing group having the maximum effect on potency. Replacement of thephenyl ring in the benzyl group by heterocyclic moieties resulted in the development ofcompounds with moderate activity for the DAT. Two most potent racemic compounds wereseparated by a diastereoisomeric separation procedure, and differential affinities were observedfor the enantiomers. Absolute configuration of the enantiomers was obtained unambiguouslyby X-ray crystal structural study. One of the enantiomers, compound S,S-(−)-19a, exhibitedthe highest potency for the DAT (IC50 = 11.3 nM) among all the compounds tested and was aspotent as GBR 12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine).However, the compound (−)-19a was more selective than GBR 12909 in binding to the DATcompared with binding to the SERT and NET. The present results establish the newly developed3,6-disubstituted piperidine derivatives as a novel template for high-affinity inhibitors of DAT.Structurally these molecules are more constrained compared to our earlier flexible piperidinemolecules and, thus, should provide more insights about their bioactive conformations.
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