title: Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation.
abstract: The forebrain cholinergic system promotes higher brain function in part by signaling through the M(1) muscarinic acetylcholine receptor (mAChR). During Alzheimer's disease (AD), these cholinergic neurons degenerate, therefore selectively activating M(1) receptors could improve cognitive function in these patients while avoiding unwanted peripheral responses associated with non-selective muscarinic agonists. We describe here benzyl quinolone carboxylic acid (BQCA), a highly selective allosteric potentiator of the M(1) mAChR. BQCA reduces the concentration of ACh required to activate M(1) up to 129-fold with an inflection point value of 845 nM. No potentiation, agonism, or antagonism activity on other mAChRs is observed up to 100 microM. Furthermore studies in M(1)(-/-) mice demonstrates that BQCA requires M(1) to promote inositol phosphate turnover in primary neurons and to increase c-fos and arc RNA expression and ERK phosphorylation in the brain. Radioligand-binding assays, molecular modeling, and site-directed mutagenesis experiments indicate that BQCA acts at an allosteric site involving residues Y179 and W400. BQCA reverses scopolamine-induced memory deficits in contextual fear conditioning, increases blood flow to the cerebral cortex, and increases wakefulness while reducing delta sleep. In contrast to M(1) allosteric agonists, which do not improve memory in scopolamine-challenged mice in contextual fear conditioning, BQCA induces beta-arrestin recruitment to M(1), suggesting a role for this signal transduction mechanism in the cholinergic modulation of memory. In summary, BQCA exploits an allosteric potentiation mechanism to provide selectivity for the M(1) receptor and represents a promising therapeutic strategy for cognitive disorders.
authors.affiliation: Alzheimer's Research, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Ma
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Seager
authors.forename: Matthew
authors.initials: M
authors.lastname: Seager
authors.forename: Marion
authors.initials: M
authors.lastname: Wittmann
authors.forename: Marlene
authors.initials: M
authors.lastname: Jacobson
authors.forename: Denise
authors.initials: D
authors.lastname: Bickel
authors.forename: Maryann
authors.initials: M
authors.lastname: Burno
authors.forename: Keith
authors.initials: K
authors.lastname: Jones
authors.forename: Valerie Kuzmick
authors.initials: VK
authors.lastname: Graufelds
authors.forename: Guangping
authors.initials: G
authors.lastname: Xu
authors.forename: Michelle
authors.initials: M
authors.lastname: Pearson
authors.forename: Alexander
authors.initials: A
authors.lastname: McCampbell
authors.forename: Renee
authors.initials: R
authors.lastname: Gaspar
authors.forename: Paul
authors.initials: P
authors.lastname: Shughrue
authors.forename: Andrew
authors.initials: A
authors.lastname: Danziger
authors.forename: Christopher
authors.initials: C
authors.lastname: Regan
authors.forename: Rose
authors.initials: R
authors.lastname: Flick
authors.forename: Danette
authors.initials: D
authors.lastname: Pascarella
authors.forename: Susan
authors.initials: S
authors.lastname: Garson
authors.forename: Scott
authors.initials: S
authors.lastname: Doran
authors.forename: Constantine
authors.initials: C
authors.lastname: Kreatsoulas
authors.forename: Lone
authors.initials: L
authors.lastname: Veng
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: William
authors.initials: W
authors.lastname: Shipe
authors.forename: Scott
authors.initials: S
authors.lastname: Kuduk
authors.forename: Cyrille
authors.initials: C
authors.lastname: Sur
authors.forename: Gene
authors.initials: G
authors.lastname: Kinney
authors.forename: Guy R
authors.initials: GR
authors.lastname: Seabrook
authors.forename: William J
authors.initials: WJ
authors.lastname: Ray
mesh_terms: D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D020013:Calcium Signaling / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D005239:Fear / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D008253:Macaca mulatta; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D015363:Quinolones / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012890:Sleep / Q000187:drug effects / Q000502:physiology
chemical_list: D007295:Inositol Phosphates; D015363:Quinolones; D043643:Receptor, Muscarinic M1; D011994:Recombinant Proteins