1. Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists
- Author
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Tikva Carrick, Julia N. Heinrich, John A. Butera, Karen L. Marquis, Scott Christian Mayer, Eugene Tseng, Tim Lock, Shaiu-Ching Sun, Albert J. Uveges, Dianne Kowal, Angela Kramer, Mark H. Pausch, and Michael Popiolek
- Subjects
Pharmacology ,Agonist ,Receptor, Muscarinic M3 ,medicine.medical_specialty ,Chemistry ,medicine.drug_class ,Receptors, Dopamine D2 ,Receptor, Muscarinic M1 ,Muscarinic acetylcholine receptor M1 ,Muscarinic Agonists ,Talsaclidine ,Sabcomeline ,Ligands ,Cevimeline ,chemistry.chemical_compound ,Endocrinology ,Internal medicine ,Muscarinic acetylcholine receptor ,Receptor, Serotonin, 5-HT2B ,medicine ,Muscarinic acetylcholine receptor M4 ,Xanomeline ,medicine.drug ,Protein Binding - 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.
- Published
- 2008