Synthesis and in vitro binding studies of substituted piperidine naphthamides. Part II: Influence of the substitution on the benzyl moiety on the affinity for D2L, D4.2, and 5-HT2A receptors

In continuation of our work on N-(piperidin-4-yl)-naphthamides, the effect of substituted benzyl groups on D2L, D4.2, and 5-HT2A receptor affinity was evaluated. In the 1-naphthamide series most compounds were highly selective for D4.2 over D2L and 5-HT2A receptors. Halogen and methyl substitution in position 3 or 4 of the benzyl group increased D4.2 affinity. In the 2-naphthamide series a similar high D4.2 over D2L selectivity was retained while 5-HT2A affinity was increased. 3-Methoxy, 3-methyl, and 4-methyl substituents were favorable for D4.2 affinity while halogens reduced affinity. 2-Naphthamides with a 3-bromo- or a 3-methyl group were mixed D4.2/5-HT2A ligands similar to their unsubstituted parent compound. All compounds from both series with significant affinity for D4.2 and 5-HT2A receptors were antagonists.

Graphical abstract1- and 2-Naphthamide derivatives: R = H, 2-Cl, 3-Cl, 4-Cl, 2-Br, 3-Br, 4-Br, 3-CF3, 4-CF3, 2,3,4,5,6-F, 4-NO2, 3-MeO, 4-MeO, 2-Me, 3-Me, 4-Me.Figure optionsDownload full-size imageDownload as PowerPoint slide