1,3-Dioxolane-based ligands incorporating a lactam or imide moiety: Structure-affinity/activity relationship at α1-adrenoceptor subtypes and at 5-HT1A receptors.

A series of 1,3-dioxolane-based compounds incorporating a lactam ( 2e4) or imide (5e7) moiety was synthesized and the pharmacological profile at a1-adrenoceptor subtypes and 5-HT1A receptor was assessed through binding and functional experiments. Starting from the 2,2-diphenyl-1,3-dioxolane derivative 1, previously shown to be a selective a1a(A)/ a1d(D)-adrenoceptor subtype antagonist, over a1b(B) subtype and 5-HT1A receptor, and replacing one phenyl ring with lactam or imide moiety a reduction of a1/5-HT1A selectivity is observed, mainly due to the increase in 5-HT1A affinity. In functional experiments lactam derivatives seems to favour 5-HT1A receptor antagonism (pKb ¼ 7.20e7.80) and a1B-adrenoceptor antagonist selectivity ( a1B/ a1A and a1B/ a1D of about 10-fold). The most interesting of the various imide derivatives is compound 7t, which is a selective a1D-adrenoceptor antagonist (pKb ¼ 8.1 and a1D/ a1A and a1D/ a1B selectivity ratios of 16 and 11 respectively) whereas at 5-HT1A receptor it is a potent partial agonist (pD2 ¼ 7.98, Emax ¼ 60%).]. Given that cis and trans diastereomer pairs for 2-7 are possible, a computational strategy based on molecular docking studies was used to elucidate the atomic details of the 5HT1A/agonist and 5HT1A/antagonist interaction.