title: Discovery of (2S,3R)-N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]benzo[b]furan-2-carboxamide (TC-5619), a selective α7 nicotinic acetylcholine receptor agonist, for the treatment of cognitive disorders.
abstract: (2S,3R)-N-[2-(Pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]benzo[b]furan-2-carboxamide (7a, TC-5619), a novel selective agonist of the α7 neuronal nicotinic acetylcholine receptor, has been identified as a promising drug candidate for the treatment of cognitive impairment associated with neurological disorders. 7a demonstrated more than a thousand-fold separation between the affinities for the α7 and α4β2 receptor subtypes and had no detectable effects on muscle or ganglionic nicotinic receptor subtypes, indicating a marked selectivity for the central nervous system over the peripheral nervous system. Results obtained from homology modeling and docking explain the observed selectivity. 7a had positive effects across cognitive, positive, and negative symptoms of schizophrenia in animal models and was additive or synergistic with the antipsychotic clozapine. Compound 7a, as an augmentation therapy to the standard treatment with antipsychotics, demonstrated encouraging results on measures of negative symptoms and cognitive dysfunction in schizophrenia and was well tolerated in a phase II clinical proof of concept trial in patients with schizophrenia.
authors.affiliation: Targacept, Inc., Winston-Salem, North Carolina 27101-4165, USA. galana99@yahoo.com
authors.forename: Anatoly A
authors.initials: AA
authors.lastname: Mazurov
authors.forename: David C
authors.initials: DC
authors.lastname: Kombo
authors.forename: Terry A
authors.initials: TA
authors.lastname: Hauser
authors.forename: Lan
authors.initials: L
authors.lastname: Miao
authors.forename: Gary
authors.initials: G
authors.lastname: Dull
authors.forename: John F
authors.initials: JF
authors.lastname: Genus
authors.forename: Nikolai B
authors.initials: NB
authors.lastname: Fedorov
authors.forename: Lisa
authors.initials: L
authors.lastname: Benson
authors.forename: Serguei
authors.initials: S
authors.lastname: Sidach
authors.forename: Yunde
authors.initials: Y
authors.lastname: Xiao
authors.forename: Philip S
authors.initials: PS
authors.lastname: Hammond
authors.forename: John W
authors.initials: JW
authors.lastname: James
authors.forename: Craig H
authors.initials: CH
authors.lastname: Miller
authors.forename: Daniel
authors.initials: D
authors.lastname: Yohannes
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis / Q000494:pharmacology*; D016466:CHO Cells; D003072:Cognition Disorders / Q000188:drug therapy*; D006224:Cricetinae; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D011812:Quinuclidines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry*; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D001572:Benzofurans; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C543641:N-(2-(pyridin-3-ylmethyl)-1-azabicyclo(2.2.2)oct-3-yl)-1-benzofuran-2-carboxamide; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor