title: The Novel, Nicotinic Alpha7 Receptor Partial Agonist, BMS-933043, Improves Cognition and Sensory Processing in Preclinical Models of Schizophrenia.
abstract: The development of alpha7 nicotinic acetylcholine receptor agonists is considered a promising approach for the treatment of cognitive symptoms in schizophrenia patients. In the present studies we characterized the novel agent, (2R)-N-(6-(1H-imidazol-1-yl)-4-pyrimidinyl)-4'H-spiro[4-azabicyclo[2.2.2]octane-2,5'-[1,3]oxazol]-2'-amine (BMS-933043), in vitro and in rodent models of schizophrenia-like deficits in cognition and sensory processing. BMS-933043 showed potent binding affinity to native rat (Ki = 3.3 nM) and recombinant human alpha7 nicotinic acetylcholine receptors (Ki = 8.1 nM) and agonist activity in a calcium fluorescence assay (EC50 = 23.4 nM) and whole cell voltage clamp electrophysiology (EC50 = 0.14 micromolar (rat) and 0.29 micromolar (human)). BMS-933043 exhibited a partial agonist profile relative to acetylcholine; the relative efficacy for net charge crossing the cell membrane was 67% and 78% at rat and human alpha7 nicotinic acetylcholine receptors respectively. BMS-933043 showed no agonist or antagonist activity at other nicotinic acetylcholine receptor subtypes and was at least 300 fold weaker at binding to and antagonizing human 5-HT3A receptors (Ki = 2,451 nM; IC50 = 8,066 nM). BMS-933043 treatment i) improved 24 hour novel object recognition memory in mice (0.1-10 mg/kg, sc), ii) reversed MK-801-induced deficits in Y maze performance in mice (1-10 mg/kg, sc) and set shift performance in rats (1-10 mg/kg, po) and iii) reduced the number of trials required to complete the extradimensional shift discrimination in neonatal PCP treated rats performing the intra-dimensional/extradimensional set shifting task (0.1-3 mg/kg, po). BMS-933043 also improved auditory gating (0.56-3 mg/kg, sc) and mismatch negativity (0.03-3 mg/kg, sc) in rats treated with S(+)ketamine or neonatal phencyclidine respectively. Given this favorable preclinical profile BMS-933043 was selected for further development to support clinical evaluation in humans.
authors.affiliation: Discovery Biology, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Bristow
authors.affiliation: Discovery Biology, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Easton
authors.affiliation: Discovery Biology, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Li
authors.affiliation: Discovery Biology, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Digavalli V
authors.initials: DV
authors.lastname: Sivarao
authors.affiliation: Discovery Biology, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Regina
authors.initials: R
authors.lastname: Lidge
authors.affiliation: Discovery Biology, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Kelli M
authors.initials: KM
authors.lastname: Jones
authors.affiliation: Discovery Biology, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Debra
authors.initials: D
authors.lastname: Post-Munson
authors.affiliation: Discovery Biology, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Daly
authors.affiliation: Discovery Biology, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lodge
authors.affiliation: Lead Discovery and Optimization, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Lizbeth
authors.initials: L
authors.lastname: Gallagher
authors.affiliation: Discovery Biology, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Thaddeus
authors.initials: T
authors.lastname: Molski
authors.affiliation: Discovery Biology, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Pieschl
authors.affiliation: Discovery Biology, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Lead Discovery and Optimization, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Adam
authors.initials: A
authors.lastname: Hendricson
authors.affiliation: Discovery Biology, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Ryan
authors.initials: R
authors.lastname: Westphal
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Cook
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Christiana
authors.initials: C
authors.lastname: Iwuagwu
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Morgan
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Benitex
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Dalton
authors.initials: D
authors.lastname: King
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Discovery Biology, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Zaczek
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb Company, Wallingford, Connecticut, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Olson
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000503:physiopathology; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018408:Patch-Clamp Techniques; D011812:Quinuclidines / Q000494:pharmacology / Q000627:therapeutic use*; D011869:Radioligand Assay; D051381:Rats; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology; D013141:Spiro Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists*
chemical_list: C000621716:BMS-933043; D011812:Quinuclidines; D013141:Spiro Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor