1,3-Dioxolane-Based Ligands as Rigid Analogues ofNaftopidil: Structure–Affinity/Activity Relationships at a1and 5-HT1A Receptors

Conformational restriction of naftopidil proved to be compatiblewith binding at a1 adrenoceptor subtypes and 5-HT receptor1A (5-HT1A), and led to the discovery of a new class of ligandswith a 1,3-dioxolane (1,3-oxathiolane, 1,3-dithiolane)structure. Compound 7 shows the highest affinity toward a1aand 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 potentcompetitive a1a and a1d adrenoceptor antagonist (pKba1A=8.24, pKba1D=8.14), whereas at 5-HT1A receptors it is a potentpartial agonist (pD2=8.30). Compounds 8 and 10 display highaffinity (pKi=8.29 and 8.26, respectively) and selectivity for 5-HT1A (5-HT1A/a1=18 and 10). In functional experiments at the5-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-dioxolane-based ligands are a versatileclass of compounds useful for the development of more selectiveligands for one (a1) or the other (5-HT1A) receptor system.