1,3-Dioxolane-based ligands as rigid analogues of Naftopidil: structure-affinity/activity relationships at alpha1 and 5-HT1A receptors.

Conformational restriction of naftopidil proved to be compatible with binding at a1 adrenoceptor subtypes and 5-HT receptor 1A (5-HT1A), 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 a1a and a1d adrenoceptor subtypes (pKia1a=9.58, pKia1d=9.09) and selectivity over 5-HT1A receptors (a1a/5-HT1A=100, a1d/5 HT1A=26). In functional experiments it behaves as a potent competitive a1a and a1d adrenoceptor antagonist (pKba1A=8.24, pKba1D=8.14), whereas at 5- HT1A receptors it is a potent partial agonist (pD2=8.30). Compounds 8 and 10 display high affinity (pKi=8.29 and 8.26, respectively) and selectivity for 5-HT1A (5-HT1A/a1=18 and 10). In functional experiments at the 5-HT1A receptor, compound 8 appears to be neutral antagonist (pKb=7.29), whereas compound 10 is a partial agonist (pD2=6.27). Therefore, 1,3-dioxolanebased ligands are a versatile class of compounds useful for the development of more selective ligands for one (a1) or the other (5-HT1A) receptor system.