title: Egis-11150: a candidate antipsychotic compound with procognitive efficacy in rodents.
abstract: Classical antipsychotics, e.g. haloperidol, chlorpromazine, are potent at controlling the positive symptoms of schizophrenia but frequently elicit extrapyramidal motor side-effects. The introduction of atypical antipsychotics such as risperidone, olanzapine and clozapine has obviated this problem, but none of the current drugs seem to improve the cognitive deficits accompanying schizophrenia. Thus there is an unmet need for agents that not only suppress the psychotic symptoms but also ameliorate the impairment of cognition. Here, we report the preclinical properties of a candidate antipsychotic, Egis-11150, that shows marked pro-cognitive efficacy. Egis-11150 displayed high affinity for adrenergic α(1), α(2c), 5-HT(2A) 5-HT₇, moderate affinity for adrenergic α(2a) and D₂ receptors. It was a functional antagonist on all of the above receptors, with the exception of 5-HT₇ receptors, where it was an inverse agonist. Phencyclidine-induced hypermotility in mice and inhibition of conditioned avoidance response in rats were assessed to estimate efficacy against the positive and social withdrawal test in rats was used to predict efficacy against the negative symptoms of schizophrenia. Passive-avoidance learning, novel object recognition and radial maze tests in rats were used to assess pro-cognitive activity, while phencyclidine-induced disruption of prepulse inhibition in mice was examined to test for effects on attention. Egis-11150 (0.01-0.3 mg/kg, ip.) was effective in all of the preclinical models of schizophrenia examined. Moreover, a robust pro-cognitive profile was apparent. In summary, work in preclinical models indicates that Egis-11150 is a potential treatment for controlling the psychosis as well as the cognitive dysfunction in schizophrenia. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
authors: Egis Pharmaceuticals PLC, Budapest, Hungary. gacsalyi.istvan@egis.hu.
authors: István
authors: I
authors: Gacsályi
authors: Katalin
authors: K
authors: Nagy
authors: Katalin
authors: K
authors: Pallagi
authors: György
authors: G
authors: Lévay
authors: László G
authors: LG
authors: Hársing
authors: Krisztina
authors: K
authors: Móricz
authors: Szabolcs
authors: S
authors: Kertész
authors: Péter
authors: P
authors: Varga
authors: József
authors: J
authors: Haller
authors: Gábor
authors: G
authors: Gigler
authors: Gábor
authors: G
authors: Szénási
authors: József
authors: J
authors: Barkóczy
authors: Judit
authors: J
authors: Bíró
authors: Michael
authors: M
authors: Spedding
authors: Ferenc A
authors: FA
authors: Antoni
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D018697:Nootropic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011724:Pyridazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: C578114:4-chloro-5-(2-(4-(6-fluoro-benzo(d)isoxazol-3-yl)-piperidin-1-yl)-ethyl-amino)-2-methyl-2H-pyridazin-3-one; D058668:Adrenergic alpha-1 Receptor Antagonists; D014150:Antipsychotic Agents; D015507:Drugs, Investigational; D018697:Nootropic Agents; D010880:Piperidines; D011724:Pyridazines; D058830:Serotonin 5-HT2 Receptor Antagonists