1,3-Dioxolane-Based Ligands as Rigid Analogues of Naftopidil: Structure–Affinity/Activity Relationships at α1 and 5-HT1A Receptors

✍ Scribed by Claudia Sorbi; Silvia Franchini; Annalisa Tait; Adolfo Prandi; Rossella Gallesi; Piero Angeli; Gabriella Marucci; Lorenza Pirona; Elena Poggesi; Livio Brasili

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 246 KB
• Volume: 4
• Category: Article
• ISSN: 1860-7179
• DOI: 10.1002/cmdc.200800277

✦ Synopsis

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.