title: 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.
authors.affiliation: Discovery Neuroscience, Wyeth Research, CN-8000, Princeton, NJ 08543, USA.
authors.forename: Julia N
authors.initials: JN
authors.lastname: Heinrich
authors.forename: John A
authors.initials: JA
authors.lastname: Butera
authors.forename: Tikva
authors.initials: T
authors.lastname: Carrick
authors.forename: Angela
authors.initials: A
authors.lastname: Kramer
authors.forename: Dianne
authors.initials: D
authors.lastname: Kowal
authors.forename: Tim
authors.initials: T
authors.lastname: Lock
authors.forename: Karen L
authors.initials: KL
authors.lastname: Marquis
authors.forename: Mark H
authors.initials: MH
authors.lastname: Pausch
authors.forename: Mike
authors.initials: M
authors.lastname: Popiolek
authors.forename: Shaiu-Ching
authors.initials: SC
authors.lastname: Sun
authors.forename: Eugene
authors.initials: E
authors.lastname: Tseng
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Uveges
authors.forename: Scott C
authors.initials: SC
authors.lastname: Mayer
mesh_terms: D008024:Ligands; D018721:Muscarinic Agonists / Q000009:adverse effects / Q000494:pharmacology*; D011485:Protein Binding; D043643:Receptor, Muscarinic M1 / Q000819:agonists*; D043587:Receptor, Muscarinic M3 / Q000819:agonists*; D044403:Receptor, Serotonin, 5-HT2B / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism
chemical_list: D008024:Ligands; D018721:Muscarinic Agonists; D043643:Receptor, Muscarinic M1; D043587:Receptor, Muscarinic M3; D044403:Receptor, Serotonin, 5-HT2B; D017448:Receptors, Dopamine D2