1,3-Dioxolane-Based Ligands Incorporating a Lactam or Imide moiety: Structure-Affinity/Activity Relationship at alpha1–Adrenoceptor subtypes and at 5-HT1A Receptors

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 alpha1-adrenoceptor subtypes and 5-HT1A receptor was assessed through binding and functional experiments. Starting from the 2,2-diphenyl-1,3-dioxolanederivative 1, previously shown to be a selective alpha1a(A)/alpha1d(D)-adrenoceptor subtype antagonist, overalpha1b(B) subtype and 5-HT1A receptor, and replacing one phenyl ring with lactam or imide moiety a reduction of alpha1/ 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 =7.20-7.80) and alpha1B-adrenoceptor antagonist selectivity (alpha1B/alpha1A and alpha1B/alpha1D of about 10-fold). Themost interesting of the various imide derivatives is compound 7t, which is a selective alpha1Dadrenoceptorantagonist (pKb = 8.1 and alpha1D/alpha1A and alpha1D/alpha1B selectivity ratios of 16 and 11respectively) whereas at 5-HT1A receptor it is a potent partial agonist (pD2 = 7.98, Emax = 60%).].Given that cis and trans diastereomer pairs for 2-7 are possible, a computational strategy based onmolecular docking studies was used to elucidate the atomic details of the 5HT1A /agonist and 5HT1A/antagonist interaction.