ABSTRACT
Pharmacophore-based structural identification, synthesis, and structure-activity relationships of a new class of muscarinic M3 receptor antagonists, the diaryl imidazolidin-2-one derivatives, are described. The versatility of the discovered scaffold allowed for several structural modifications that resulted in the discovery of two distinct classes of compounds, specifically a class of tertiary amine derivatives (potentially useful for the treatment of overactive bladder by oral administration) and a class of quaternary ammonium salt derivatives (potentially useful for the treatment of respiratory diseases by the inhalation route of administration). In this paper, we describe the synthesis and biological activity of tertiary amine derivatives. For these compounds, selectivity for the M3 receptor toward the M2 receptor was crucial, because the M2 receptor subtype is mainly responsible for adverse systemic side effects of currently marketed muscarinic antagonists. Compound 50 showed the highest selectivity versus M2 receptor, with binding affinity for M3 receptor Ki = 4.8 nM and for M2 receptor Ki = 1141 nM. Functional in vitro studies on selected compounds confirmed the antagonist activity toward the M3 receptor and functional selectivity toward the M2 receptor.
Subject(s)
Imidazolidines/chemical synthesis , Receptor, Muscarinic M3/antagonists & inhibitors , Administration, Oral , Animals , Atrial Function/drug effects , CHO Cells , Caco-2 Cells , Cell Membrane Permeability , Cricetinae , Cricetulus , Female , Humans , Imidazolidines/chemistry , Imidazolidines/pharmacology , In Vitro Techniques , Male , Mice , Microsomes/metabolism , Models, Molecular , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Radioligand Assay , Rats , Receptor, Muscarinic M2/antagonists & inhibitors , Structure-Activity Relationship , Urinary Bladder/drug effects , Urinary Bladder/physiologyABSTRACT
Synthesis and biological activity of a novel class of quaternary ammonium salt muscarinic M3 receptor antagonists, showing high selectivity versus the M2 receptor, are described. Selected compounds exhibited potent anticholinergic properties, in isolated guinea-pig trachea, and good functional selectivity for trachea over atria. In vivo, the same compounds potently inhibited acetylcholine-induced bronchoconstriction after intratracheal administration in the guinea pig.