title: Discovery and structure-activity relationship of quinuclidine benzamides as agonists of alpha7 nicotinic acetylcholine receptors.
abstract: A library of benzamides was tested for alpha7 nicotinic acetylcholine receptor (nAChR) agonist activity using a chimeric receptor in a functional, cell-based, high-throughput assay. From this library, quinuclidine benzamides were found to have alpha7 nAChR agonist activity. The SAR diverged from the activity of this compound class verses the 5-HT(3) receptor, a structural homologue of the alpha7 nAChR. PNU-282987, the most potent compound from this series, was also shown to open native alpha7 nAChRs in cultured rat neurons and to reverse an amphetamine-induced gating deficit in rats.
authors.affiliation: Department of Neuroscience, Global Research and Development, Pfizer Inc., Groton, CT, USA.
authors.forename: Alice L
authors.initials: AL
authors.lastname: Bodnar
authors.forename: Luz A
authors.initials: LA
authors.lastname: Cortes-Burgos
authors.forename: Karen K
authors.initials: KK
authors.lastname: Cook
authors.forename: Dac M
authors.initials: DM
authors.lastname: Dinh
authors.forename: Vincent E
authors.initials: VE
authors.lastname: Groppi
authors.forename: Mihaly
authors.initials: M
authors.lastname: Hajos
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Higdon
authors.forename: William E
authors.initials: WE
authors.lastname: Hoffmann
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Hurst
authors.forename: Jason K
authors.initials: JK
authors.lastname: Myers
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Rogers
authors.forename: Theron M
authors.initials: TM
authors.lastname: Wall
authors.forename: Mark L
authors.initials: ML
authors.lastname: Wolfe
authors.forename: Erik
authors.initials: E
authors.lastname: Wong
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D020650:Combinatorial Chemistry Techniques; D006624:Hippocampus / Q000166:cytology; D015640:Ion Channel Gating / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D058827:Serotonin 5-HT3 Receptor Agonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D001549:Benzamides; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D058827:Serotonin 5-HT3 Receptor Agonists; D064569:alpha7 Nicotinic Acetylcholine Receptor