title: AC-260584, an orally bioavailable M(1) muscarinic receptor allosteric agonist, improves cognitive performance in an animal model.
abstract: The recent discovery of allosteric potentiators and agonists of the muscarinic M(1) receptor represents a significant advance in the muscarinic receptor pharmacology. In the current study we describe the receptor pharmacology and pro-cognitive action of the allosteric agonist AC-260584. Using in vitro cell-based assays with cell proliferation, phosphatidylinositol hydrolysis or calcium mobilization as endpoints, AC-260584 was found to be a potent (pEC(50) 7.6-7.7) and efficacious (90-98% of carbachol) muscarinic M(1) receptor agonist. Furthermore, as compared to orthosteric binding agonists, AC-260584 showed functional selectivity for the M(1) receptor over the M(2), M(3), M(4) and M(5) muscarinic receptor subtypes. Using GTPgammaS binding assays, its selectivity was found to be similar in native tissues expressing mAChRs to its profile in recombinant systems. In rodents, AC-260584 activated extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation in the hippocampus, prefrontal cortex and perirhinal cortex. The ERK1/2 activation was dependent upon muscarinic M(1) receptor activation since it was not observed in M(1) knockout mice. AC-260584 also improved the cognitive performance of mice in the novel object recognition assay and its action is blocked by the muscarinic receptor antagonist pirenzepine. Taken together these results indicate for the first time that a M(1) receptor agonist selective over the other mAChR subtypes can have a symptomatically pro-cognitive action. In addition, AC-260584 was found to be orally bioavailable in rodents. Therefore, AC-260584 may serve as a lead compound in the development of M(1) selective drugs for the treatment of cognitive impairment associated with schizophrenia and Alzheimer's disease.
authors.affiliation: ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Blvd., San Diego, CA 92129, USA. stefania_bradley@merck.com
authors.forename: Stefania Risso
authors.initials: SR
authors.lastname: Bradley
authors.forename: Jelveh
authors.initials: J
authors.lastname: Lameh
authors.forename: Linda
authors.initials: L
authors.lastname: Ohrmund
authors.forename: Thomas
authors.initials: T
authors.lastname: Son
authors.forename: Abhishek
authors.initials: A
authors.lastname: Bajpai
authors.forename: Derek
authors.initials: D
authors.lastname: Nguyen
authors.forename: Mikael
authors.initials: M
authors.lastname: Friberg
authors.forename: Ethan S
authors.initials: ES
authors.lastname: Burstein
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Spalding
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Ott
authors.forename: Hans H
authors.initials: HH
authors.lastname: Schiffer
authors.forename: Ali
authors.initials: A
authors.lastname: Tabatabaei
authors.forename: Krista
authors.initials: K
authors.lastname: McFarland
authors.forename: Robert E
authors.initials: RE
authors.lastname: Davis
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Bonhaus
mesh_terms: D000284:Administration, Oral; D000818:Animals; D048588:Benzoxazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D041681:NIH 3T3 Cells; D018697:Nootropic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
chemical_list: D048588:Benzoxazines; D018721:Muscarinic Agonists; D018697:Nootropic Agents; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; C516553:4-(3-(4-butylpiperidin-1-yl)propyl)-7-fluoro-4H-benzo(1,4)oxazin-3-one