title: TC-5619: an alpha7 neuronal nicotinic receptor-selective agonist that demonstrates efficacy in animal models of the positive and negative symptoms and cognitive dysfunction of schizophrenia.
abstract: A growing body of evidence suggests that the alpha7 neuronal nicotinic receptor (NNR) subtype is an important target for the development of novel therapies to treat schizophrenia, offering the possibility to address not only the positive but also the cognitive and negative symptoms associated with the disease. In order to probe the relationship of alpha7 function to relevant behavioral correlates we employed TC-5619, a novel selective agonist for the alpha7 NNR subtype. TC-5619 binds with very high affinity to the alpha7 subtype and is a potent full agonist. TC-5619 has little or no activity at other nicotinic receptors, including the alpha4beta2, ganglionic (alpha3beta4) and muscle subtypes. The transgenic th(tk-)/th(tk-) mouse model that reflects many of the developmental, anatomical, and multi-transmitter biochemical aspects of schizophrenia was used to assess the antipsychotic effects of TC-5619. In these mice TC-5619 acted both alone and synergistically with the antipsychotic clozapine to correct impaired pre-pulse inhibition (PPI) and social behavior which model positive and negative symptoms, respectively. Antipsychotic and cognitive effects of TC-5619 were also assessed in rats. Similar to the results in the transgenic mice, TC-5619 significantly reversed apomorphine-induced PPI deficits. In a novel object recognition paradigm in rats TC-5619 demonstrated long-lasting enhancement of memory over a wide dose range. These results suggest that alpha7-selective agonists such as TC-5619, either alone or in combination with antipsychotics, could offer a new approach to treating the constellation of symptoms associated with schizophrenia, including cognitive dysfunction.
authors.affiliation: Preclinical Research, Targacept, Inc, Winston-Salem, NC 27101, USA. Terry.Hauser@Targacept.com
authors.forename: T A
authors.initials: TA
authors.lastname: Hauser
authors.forename: A
authors.initials: A
authors.lastname: Kucinski
authors.forename: K G
authors.initials: KG
authors.lastname: Jordan
authors.forename: G J
authors.initials: GJ
authors.lastname: Gatto
authors.forename: S R
authors.initials: SR
authors.lastname: Wersinger
authors.forename: R A
authors.initials: RA
authors.lastname: Hesse
authors.forename: E K
authors.initials: EK
authors.lastname: Stachowiak
authors.forename: M K
authors.initials: MK
authors.lastname: Stachowiak
authors.forename: R L
authors.initials: RL
authors.lastname: Papke
authors.forename: P M
authors.initials: PM
authors.lastname: Lippiello
authors.forename: M
authors.initials: M
authors.lastname: Bencherif
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects*; D001572:Benzofurans / Q000494:pharmacology / Q000627:therapeutic use*; D003024:Clozapine / Q000494:pharmacology / Q000627:therapeutic use; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D018722:Nicotinic Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D011401:Promoter Regions, Genetic; D011812:Quinuclidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000096:biosynthesis / Q000235:genetics; D011978:Receptors, Nicotinic / Q000502:physiology*; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D012565:Schizophrenic Psychology; D012919:Social Behavior; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D014150:Antipsychotic Agents; D001572:Benzofurans; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; C543641:N-(2-(pyridin-3-ylmethyl)-1-azabicyclo(2.2.2)oct-3-yl)-1-benzofuran-2-carboxamide; D018722:Nicotinic Agonists; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D014446:Tyrosine 3-Monooxygenase; D051496:Receptor, Fibroblast Growth Factor, Type 1; D003024:Clozapine