Functional comparison of muscarinic partial agonists at muscarinic receptor subtypes hM₁, hM₂, hM₃, hM₄ and hM₅ using microphysiometry

This study describes the pharmacological comparison of the muscarinic partial agonists sabcomeline, xanomeline and milameline at human cloned muscarinic receptor subtypes (hM 1–5 ). Radioligand binding studies at the hM 1–5 muscarinic receptor subtypes were compared with functional studies using microphysiometry using carbachol as the standard full agonist. In binding assays none of the compounds studied displayed preferential affinity for the M 1,3,4 or M 5 subtypes although carbachol was less potent at hM 1 than hM 3,4,5 . In functional studies, all of the compounds studied displayed similar levels of efficacy across the muscarinic receptors with the exception of M 3 , where there was a large apparent receptor reserve and the compounds behaved essentially as full agonists. Sabcomeline was the most potent agonist in functional studies but also showed the lowest efficacy. In terms of potency, xanomeline showed some selectivity for M 1 over M 2 receptors and milameline showed some selectivity for M 2 over M 1 receptors. These results show the value of microphysiometry in being able to compare receptor pharmacology across subtypes irrespective of the signal transduction pathway. None of the partial agonists showed functional selectivity for M 1 receptors, or indeed any muscarinic receptor, in the present study. British Journal of Pharmacology (1999) 126 , 1620–1624; doi: 10.1038/sj.bjp.0702463