1,3‐Dioxolane‐Based Ligands as Rigid Analogues of Naftopidil: Structure–Affinity/Activity Relationships at α₁ and 5‐HT_1A Receptors

Abstract

Abstract 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. magnified image 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.