1,3‐Dioxolane‐Based Ligands as Rigid Analogues of Naftopidil: Structure–Affinity/Activity Relationships at α 1 and 5‐HT 1A Receptors

Conformational restriction of naftopidil led to the discovery of a new class of ligands with a 1,3‐dioxolane (1,3‐oxathiolane, 1,3‐dithiolane) structure that bind to α 1 adrenoceptor subtypes and 5‐HT 1A receptors. Adequate structural modifications address the selectivity toward one or the other receptor system.Conformational restriction of naftopidil proved to be compatible with binding at α 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 α 1a and α 1d adrenoceptor subtypes (p K i  α 1a =9.58, p K i  α 1d =9.09) and selectivity over 5‐HT 1A receptors (α 1a /5‐HT 1A =100, α 1d /5‐HT 1A =26). In functional experiments it behaves as a potent competitive α 1a and α 1d adrenoceptor antagonist (p K b  α 1A =8.24, p K b  α 1D =8.14), whereas at 5‐HT 1A receptors it is a potent partial agonist (p D 2 =8.30). Compounds 8 and 10 display high affinity (p K i =8.29 and 8.26, respectively) and selectivity for 5‐HT 1A (5‐HT 1A /α 1 =18 and 10). In functional experiments at the 5‐HT 1A receptor, compound 8 appears to be neutral antagonist (p K b =7.29), whereas compound 10 is a partial agonist (p D 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 (α 1 ) or the other (5‐HT 1A ) receptor system.