title: Discovery of potential antipsychotic agents possessing pro-cognitive properties.
abstract: Current antipsychotic drug therapies for schizophrenia have limited efficacy and are notably ineffective at addressing the cognitive deficits associated with this disorder. The present study was designed to develop effective antipsychotic agents that would also ameliorate the cognitive deficits associated with this disease. In vitro studies comprised of binding and functional assays were utilized to identify compounds with the receptor profile that could provide both antipsychotic and pro-cognitive features. Antipsychotic and cognitive models assessing in vivo activity of these compounds included locomotor activity assays and novel object recognition assays. We developed a series of potential antipsychotic agents with a novel receptor activity profile comprised of muscarinic M(1) receptor agonism in addition to dopamine D(2) antagonism and serotonin 5-HT(2A) inverse agonism. Like other antipsychotic agents, these compounds reverse both amphetamine and dizocilpine-induced hyperactivity in animals. In addition, unlike other antipsychotic drugs, these compounds demonstrate pro-cognitive actions in the novel object recognition assay. The dual attributes of antipsychotic and pro-cognitive actions distinguish these compounds from other antipsychotic drugs and suggest that these compounds are prototype molecules in the development of novel pro-cognitive antipsychotic agents.
authors.affiliation: ACADIA Pharmaceuticals, Inc, San Diego, CA 92121, USA. jelameh@yahoo.com
authors.forename: Jelveh
authors.initials: J
authors.lastname: Lameh
authors.forename: Krista
authors.initials: K
authors.lastname: McFarland
authors.forename: Jorgen
authors.initials: J
authors.lastname: Ohlsson
authors.forename: Fredrik
authors.initials: F
authors.lastname: Ek
authors.forename: Fabrice
authors.initials: F
authors.lastname: Piu
authors.forename: Ethan S
authors.initials: ES
authors.lastname: Burstein
authors.forename: Ali
authors.initials: A
authors.lastname: Tabatabaei
authors.forename: Roger
authors.initials: R
authors.lastname: Olsson
authors.forename: Stefania Risso
authors.initials: SR
authors.lastname: Bradley
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Bonhaus
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects*; D065127:Dopamine D2 Receptor Antagonists; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D041681:NIH 3T3 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000819:agonists; D044402:Receptor, Serotonin, 5-HT2A; D021641:Recognition, Psychology / Q000187:drug effects; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D043643:Receptor, Muscarinic M1; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists
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