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

Abstract A series of 1,3-dioxolane-based compounds incorporating a lactam ( 2 – 4 ) or imide ( 5 – 7 ) moiety was synthesized and the pharmacological profile at α 1 -adrenoceptor subtypes and 5-HT 1A 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 α 1a(A) /α 1d(D) -adrenoceptor subtype antagonist, over α 1b(B) subtype and 5-HT 1A receptor, and replacing one phenyl ring with lactam or imide moiety a reduction of α 1 /5-HT 1A selectivity is observed, mainly due to the increase in 5-HT 1A affinity. In functional experiments lactam derivatives seems to favour 5-HT 1A receptor antagonism (pKb = 7.20–7.80) and α 1B -adrenoceptor antagonist selectivity (α 1B /α 1A and α 1B /α 1D of about 10-fold). The most interesting of the various imide derivatives is compound 7t , which is a selective α 1D -adrenoceptor antagonist (pKb = 8.1 and α 1D /α 1A and α 1D /α 1B selectivity ratios of 16 and 11 respectively) whereas at 5-HT 1A receptor it is a potent partial agonist (pD2 = 7.98, E max  = 60%).]. Given that cis and tran s diastereomer pairs for 2-7 are possible, a computational strategy based on molecular docking studies was used to elucidate the atomic details of the 5HT 1A /agonist and 5HT 1A /antagonist interaction.