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 D2L, D4.2, and 5-HT2A receptors. Different compounds display selectivity for D4.2 and 5-HT2A receptors versus D2L 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 D4.2 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 D4.2 ligand (7) possesses a phenylpropyl moiety while its affinity for 5-HT2A receptors is strongly reduced. All compounds with significant affinity for D4.2 and 5-HT2A receptors were antagonists.

Graphical abstractR = benzyl, 2-phenethyl, 1-phenethyl, 3-phenylpropyl, (S)-3-(1-hydroxy-1-phenyl)propyl, (R)-3-(1-hydroxy-1-phenyl)propyl, 4-phenylbutyl.Figure optionsDownload full-size imageDownload as PowerPoint slide