Synthesis and in vitro binding studies of substituted piperidine naphthamides.: Part I:: Influence of the substitution on the basic nitrogen and the position of the amide on the affinity for D2L, D4.2, and 5-HT2A receptors

A series of 1- and 2-naphthamides has been prepared and tested for in vitro binding to D-2L, D-4.2, and 5-HT2A receptors. Different compounds display selectivity for D-4.2 and 5-HT2A receptors versus D-2L receptors. N-(1-Arylalkyl-piperidin-4-yl) carboxamides have higher affinities than the corresponding N-(4-arylalkylamino-piperidin-1-yl) carboxamide analogues. A benzyl moiety in position 1 of the piperidine in the 2-naphthamide series (2) appears to be the best choice for a favorable interaction with D-4.2 and 5-HT2A receptors. Increasing the linker length between the phenyl ring and the basic nitrogen led to a decreased affinity for these receptors. In the 1-naphthamide series, the most potent D-4.2 ligand (7) possesses a phenylpropyl moiety while its affinity for 5-HT2A receptors is strongly reduced. All compounds with significant affinity for D-4.2 and 5-HT2A receptors were antagonists. (c) 2007 Elsevier Ltd. All rights reserved.