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

Julia N Heinrich, John A Butera, Tikva Carrick, Angela Kramer, Dianne Kowal, Tim Lock, Karen L Marquis, Mark H Pausch, Mike Popiolek, Shaiu-Ching Sun, Eugene Tseng, Albert J Uveges, Scott C Mayer

Discovery Neuroscience, Wyeth Research, CN-8000, Princeton, NJ 08543, USA.

European journal of pharmacology 2009 Mar 1

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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.

Citation

Julia N Heinrich, John A Butera, Tikva Carrick, Angela Kramer, Dianne Kowal, Tim Lock, Karen L Marquis, Mark H Pausch, Mike Popiolek, Shaiu-Ching Sun, Eugene Tseng, Albert J Uveges, Scott C Mayer. Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists. European journal of pharmacology. 2009 Mar 1;605(1-3):53-6