Discovery of potent α1L-adrenoceptor agonists: Design and synthesis of bicyclic derivatives.

We aimed to create a novel and potent α(1L)-adrenoceptor agonist because such agonists are possible drug candidates for stress urinary incontinence. We used ligand-based drug design and evaluated the α(1L)-adrenoceptor agonist activity of the designed compounds. Among them, tetrahydroquinoline derivative 50 showed the most potent activity (ratio of noradrenaline half maximal effective concentration, 0.0028) and effectively induced contraction of rat bladder neck.

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 alpha(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 alpha(1a(A))/alpha(1d(D))-adrenoceptor subtype antagonist, over alpha(1b(B)) subtype and 5-HT(1A) receptor, and replacing one phenyl ring with lactam or imide moiety a reduction of alpha(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 alpha(1B)-adrenoceptor antagonist selectivity (alpha(1B)/alpha(1A) and alpha(1B)/alpha(1D) of about 10-fold). The most interesting of the various imide derivatives is compound 7t, which is a selective alpha(1D)-adrenoceptor antagonist (pKb = 8.1 and alpha(1D)/alpha(1A) and alpha(1D)/alpha(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 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 5HT(1A)/agonist and 5HT(1A)/antagonist interaction.