Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists.

Abstract In functional assay assessments using the five muscarinic receptor subtypes, a second generation of muscarinic M 1 -preferring receptor agonists [AC-42 ( 1 ), AC-260584 ( 2 ), 77-LH-28-1 ( 3 ) and LY-593039 ( 4 )] was shown to have higher selectivity for muscarinic M 1 over M 3 receptor as compared to historical agonists [talsaclidine ( 8 ), sabcomeline ( 10 ), xanomeline ( 11 ), WAY-132983 ( 12 ), cevimeline ( 9 ) and NGX-267 ( 6 )]. Another striking difference of these more recent compounds is their affinities for the dopamine D 2 and 5-HT 2B receptors. Taken together, these results suggest that the newer compounds may have a greater clinical safety profile, especially with regard to muscarinic M 3 receptor-mediated events, than the historical agonists, but their affinities for other receptors may still compromise their use to validate the therapeutic potential of muscarinic M 1 receptor agonists.