N-substituted quinuclidinol esters as potential therapeutic antimuscarinic agents

Abstract

Chronic obstructive pulmonary disease, irritable bowel syndrome and urinary incontinence are substantial medical conditions that show symptomatic improvement when treated with peripherally acting muscarinic antagonists. The target for these agents is the M₃ muscarinic receptor whose over-activity in peripheral autonomic tissues contributes to the unwanted symptoms of cholinergic stimulation. This patent describes a series of N-substituted quinuclidinol esters of acetic acid derivatives that differ from prior antagonists by the introduction of large moieties to the quaternary nitrogen. These agents were shown to exhibit high affinity for the human M₃ muscarinic receptor; their affinity for other muscarinic subtypes was not described. It is possible that an antagonist exhibiting selectivity for both M₂ and M₃ receptors would be preferred because the M₂ receptor also contributes to contraction in the smooth muscle of the airways, intestines and urinary bladder.

• chronic obstructive pulmonary disease
• incontinence
• irritable bowel syndrome
• muscarinic antagonists
• muscarinic receptors
• quinuclidine