title: Development of spiroguanidine-derived α7 neuronal nicotinic receptor partial agonists.
abstract: We describe the synthesis of quinuclidine-containing spiroguanidines and their utility as α7 neuronal nicotinic acetylcholine receptor (nAChR) partial agonists. The convergent synthetic route developed for this study allowed for rapid SAR investigation and provided access to a structurally diverse set of analogs. A potent and selective α7 nAChR partial agonist, N-(6-methyl-1,3-benzoxazol-2-yl)-3',5'-dihydro-4-azaspiro[bicyclo[2.2.2]octane-2,4'-imidazole]-2'-amine (BMS-910731, 16), was identified. This compound induced immediate early genes c-fos and Arc in a preclinical rodent model of α7 nAChR-derived cellular activation and plasticity. Importantly, the ability to incorporate selectivity for the α7 nACh receptor over the 5-HT3Areceptor in this series suggested a significant difference in steric requirements between the two receptors.
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA. Electronic address: matthew.hill@bms.com.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hill
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Haiquan
authors.initials: H
authors.lastname: Fang
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Sivarao V
authors.initials: SV
authors.lastname: Digavalli
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Francine L
authors.initials: FL
authors.lastname: Healy
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Lizbeth
authors.initials: L
authors.lastname: Gallagher
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Debra
authors.initials: D
authors.lastname: Post-Munson
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Natale
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Benitex
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Morgan
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Lodge
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Bristow
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Olson
mesh_terms: D004305:Dose-Response Relationship, Drug; D019791:Guanidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D011812:Quinuclidines / Q000737:chemistry / Q000494:pharmacology*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists*
chemical_list: D011812:Quinuclidines; D013141:Spiro Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor; D019791:Guanidine
keywords: 5-HT(3A) receptor; Immediate early genes; Schizophrenia; Spiroguanidine; α7 nicotinic acetylcholine receptor