1,3-Dioxolane-based compounds (2-14) were synthesized, and the pharmacological profiles at alpha(1)-adrenoceptor subtypes were assessed by functional experiments in isolated rat vas deferens (alpha(1A)), spleen (alpha(1B)), and aorta (alpha(1D)). Compound 9, with a pA(2) of 7.53, 7.36, and 8.65 at alpha(1A), alpha(1B), and alpha(1D), respectively, is the most potent antagonist of the series, while compound 10 with a pA(2) of 8.37 at alpha(1D) subtype and selectivity ratios of 162 (alpha(1D)/alpha(1A)) and 324 (alpha(1D)/alpha(1B)) is the most selective. Binding assays in CHO cell membranes expressing human cloned alpha(1)-adrenoceptor subtypes confirm the pharmacological profiles derived from functional experiments, although the selectivity values are somewhat lower. Therefore, it is concluded that 1,3-dioxolane-based ligands are a new class of alpha(1)-adrenoceptor antagonists.

Several recent studies have focused on a detailed analysis of the trace amine-associated receptor type 5 (TAAR5) pharmacology, up to now revealing only a limited number of species-specific ligands, which are also active towards other TAAR receptors. In this context, we developed our work on TAAR5 applying a structure-based computational protocol, revolving around homology modeling and virtual screening calculations. In detail, mTAAR5 and hTAAR5 homology models were built, in order to explore any pattern of structural requirements which could be involved in species-specific differences. Successively, the mTAAR5 model was employed to perform a virtual screening of an in-house library of compounds, including different five-membered ring derivatives, linked to a phenyl ring through a flexible or a rigid basic moiety. The computational protocol applied allowed to select a number of chemical scaffolds that were tested in a biological assay leading to the discovery of the first two mTAAR5 antagonists

Conformational restriction of naftopidil proved to be compatible with binding at alpha(1) adrenoceptor subtypes and 5-HT receptor 1A (5-HT(1A)), and led to the discovery of a new class of ligands with a 1,3-dioxolane (1,3-oxathiolane, 1,3-dithiolane) structure. Compound 7 shows the highest affinity toward alpha(1a) and alpha(1d) adrenoceptor subtypes (pK(i) alpha(1a) = 9.58, pK(i) alpha(1d) = 9.09) and selectivity over 5-HT(1A) receptors (alpha(1a)/5-HT(1A) = 100, alpha(1d)/5-HT(1A) = 26). In functional experiments it behaves as a potent competitive alpha(1a) and alpha(1d) adrenoceptor antagonist (pK(b) alpha(1A) = 8.24, pK(b) alpha(1D) = 8.14), whereas at 5-HT(1A) receptors it is a potent partial agonist (pD(2) = 8.30). Compounds 8 and 10 display high affinity (pK(i) = 8.29 and 8.26, respectively) and selectivity for 5-HT(1A) (5-HT(1A)/alpha(1) = 18 and 10). In functional experiments at the 5-HT(1A) receptor, compound 8 appears to be neutral antagonist (pK(b) = 7.29), whereas compound 10 is a partial agonist (pD(2) = 6.27). Therefore, 1,3-dioxolane-based ligands are a versatile class of compounds useful for the development of more selective ligands for one (alpha(1)) or the other (5-HT(1A)) receptor system.