title: Using cholinergic M1 receptor positive allosteric modulators to improve memory via enhancement of brain cholinergic communication.
abstract: Benzylquinolone carboxylic acid (BQCA) is a recently described cholinergic muscarinic M(1) receptor positive allosteric modulator having potential as cognitive enhancer in dementia. The present study focused on the characterisation of BQCA's mode of action in relation to positive effects on memory and side-effects in an animal model. To get insight into this mode of action, in vitro receptor potency/left shift experiments in cells stably expressing the rat's M(1) receptor were performed. They revealed an inflection point value of BQCA corresponding to 306nM, and potentiation of the agonist response up to 47-fold in presence of 10μM of BQCA. In vivo, brain microdialysis showed a maximal brain level of 270nM, 40min after i.p. administration at 10mg/kg. Based on in vitro data obtained with this dose, it can be concluded that BQCA reaches brain levels which should potentiate the agonist response about 4-fold. Behavioural data confirmed that BQCA used at 10mg/kg attenuated scopolamine-induced memory deficit in a spontaneous alternation task. Moreover, BQCA showed no side effect at 10mg/kg and above in spontaneous locomotion and salivation tests. The profile of BQCA observed in the present study displays a clear advantage over the M(1)-M(3) agonist cevimeline. The present data show the therapeutic potential of the M(1) receptor positive allosteric modulator BQCA for the treatment of memory deficits observed in Alzheimer's disease.
authors.affiliation: In Vivo Pharmacology, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, Frankfurt am Main D-60318, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Chambon
authors.forename: Claudia
authors.initials: C
authors.lastname: Jatzke
authors.forename: Nico
authors.initials: N
authors.lastname: Wegener
authors.forename: Andreas
authors.initials: A
authors.lastname: Gravius
authors.forename: Wojciech
authors.initials: W
authors.lastname: Danysz
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002264:Carboxylic Acids / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D018721:Muscarinic Agonists / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018697:Nootropic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D015363:Quinolones / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D011812:Quinuclidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012472:Salivation / Q000187:drug effects; D012601:Scopolamine / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014162:Transfection
chemical_list: D002264:Carboxylic Acids; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D018697:Nootropic Agents; D015363:Quinolones; D011812:Quinuclidines; D043643:Receptor, Muscarinic M1; D013876:Thiophenes; D012601:Scopolamine; C059240:cevimeline; D002118:Calcium