title: 2-(Arylmethyl)-3-substituted quinuclidines as selective alpha 7 nicotinic receptor ligands.
abstract: A series of 2-(arylmethyl)-3-substituted quinuclidines was developed as alpha7 neuronal nicotinic acetylcholine receptor (nAChR) agonists based on a putative pharmacophore model. The series is highly selective for the alpha7 over other nAChRs (e.g., the alpha4beta2 of the CNS, and the muscle and ganglionic subtypes) and is functionally tunable at alpha7. One member of the series, (+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide (+)-8l), has potent agonistic activity for the alpha7 nAChR (EC(50)=33nM, I(max)=1.0), at concentrations below those that result in desensitization.
authors.affiliation: Targacept, Inc., Medicinal Chemistry, 200 East First Street, Suite 300, Winston-Salem, NC 27101, USA. anatoly.mazurov@targacept.com <anatoly.mazurov@targacept.com>
authors.forename: Anatoly
authors.initials: A
authors.lastname: Mazurov
authors.forename: Jozef
authors.initials: J
authors.lastname: Klucik
authors.forename: Lan
authors.initials: L
authors.lastname: Miao
authors.forename: Teresa Y
authors.initials: TY
authors.lastname: Phillips
authors.forename: Angela
authors.initials: A
authors.lastname: Seamans
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Schmitt
authors.forename: Terry A
authors.initials: TA
authors.lastname: Hauser
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Johnson
authors.forename: Craig
authors.initials: C
authors.lastname: Miller
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D008024:Ligands; D011812:Quinuclidines / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D008024:Ligands; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor