Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists.
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.
Heinrich
Julia N
JN
Discovery Neuroscience, Wyeth Research, CN-8000, Princeton, NJ 08543, USA.
Butera
John A
JA
Carrick
Tikva
T
Kramer
Angela
A
Kowal
Dianne
D
Lock
Tim
T
Marquis
Karen L
KL
Pausch
Mark H
MH
Popiolek
Mike
M
Sun
Shaiu-Ching
SC
Tseng
Eugene
E
Uveges
Albert J
AJ
Mayer
Scott C
SC
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
D008024:Ligands; D018721:Muscarinic Agonists; D043643:Receptor, Muscarinic M1; D043587:Receptor, Muscarinic M3; D044403:Receptor, Serotonin, 5-HT2B; D017448:Receptors, Dopamine D2