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Titolo:
S18327 (1-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperid-1-yl]ethyl}3-phenyl imidazolin-2-one), a novel, potential antipsychotic displaying marked antagonist properties at alpha(1) and alpha(2)-adrenergic receptors: I. Receptorial, neurochemical, and electrophysiological profile
Autore:
Millan, MJ; Gobert, A; Newman-Tancredi, A; Lejeune, F; Cussac, D; Rivet, JM; Audinot, V; Adhumeau, A; Brocco, M; Nicolas, JP; Boutin, JA; Despaux, N; Peglion, JL;
Indirizzi:
Ctr Rech Croissy, Dept Psychopharmacol, Inst Rech Servier, F-78290 CroissySur Seine, France Ctr Rech Croissy Croissy Sur Seine France F-78290 oissySur Seine, France Ctr Rech Croissy, Dept Mol & Cellular Pharmacol, Inst Rech Servier, F-78290 Croissy Sur Seine, France Ctr Rech Croissy Croissy Sur Seine France F-78290 issy Sur Seine, France Ctr Rech Suresnes, Inst Rech Servier, Chem Dept B, Suresnes, France Ctr Rech Suresnes Suresnes France ervier, Chem Dept B, Suresnes, France
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 1, volume: 292, anno: 2000,
pagine: 38 - 53
SICI:
0022-3565(200001)292:1<38:S(>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
MEDIAL PREFRONTAL CORTEX; DOPAMINE D-4 RECEPTORS; NUCLEUS-ACCUMBENS; SELECTIVE ANTAGONIST; MOLECULAR-BIOLOGY; 5-HT2A RECEPTORS; CLOZAPINE; RELEASE; RAT; SCHIZOPHRENIA;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
66
Recensione:
Indirizzi per estratti:
Indirizzo: Millan, MJ Ctr Rech Croissy, Dept Psychopharmacol, Inst Rech Servier, 125 Chemin de Ronde, F-78290 Croissy Sur Seine, France Ctr Rech Croissy 125 Chemin de Ronde Croissy Sur Seine France F-78290
Citazione:
M.J. Millan et al., "S18327 (1-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperid-1-yl]ethyl}3-phenyl imidazolin-2-one), a novel, potential antipsychotic displaying marked antagonist properties at alpha(1) and alpha(2)-adrenergic receptors: I. Receptorial, neurochemical, and electrophysiological profile", J PHARM EXP, 292(1), 2000, pp. 38-53

Abstract

S18327 displayed modest affinity for human (h) D-2 and hD(3) receptors andhigh affinity for hD(4) receptors. At each, S18327 antagonized stimulationof [S-35] guanosine-5'-O-(3-thio) triphosphate binding by dopamine (DA). It also blocked activation of mitogen-activated protein kinase at hD(3) receptors. The affinity of S18327 at hD(1) and hD(5) sites was modest. S18327 showed pronounced affinity for human serotonin (h5-HT)(2A) receptors and human alpha(1A)-adrenergic receptors (hARs), at which it antagonized increasesin intracellular Ca2+ concentration levels elicited by 5-HT and norepinephrine (NE), respectively. S18327 presented significant affinity for h alpha(2A)-ARs and antagonized NE-induced[S-35] guanosine-5'-O-(3-thio) triphosphate binding both at these sites and at alpha(2)-ARs in rat amygdala. Reflecting blockade of alpha(2)-autoreceptors, S18327 enhanced firing of adrenergic neurons in locus ceruleus, accelerated hippocampal synthesis of NE, and increased dialysate levels of NE in hippocampus, accumbens, and frontal cortex. S18327 abolished inhibition of ventrotegmental area-localized dopaminergic neurons by apomorphine. However, S18327 alone did not affect their activity and only modestly enhanced cerebral turnover of DA and dialysate levels of DA in striatum and accumbens. In contrast, S18327 markedly increased dialysate levels of DA in frontal cortex, an action abolished by the selective alpha(2)-AR agonist, S18616. Finally, S18327 reduced synthesis and dialysate levels of 5-HT in striatum and suppressed firing of dorsal raphe-localized serotonergic neurons, an action attenuated by the alpha(1)-AR agonist cirazoline. In conclusion, S18327 possesses marked antagonist activity at alpha(1)-ARs and D-4 and 5-HT2A receptors and less potent antagonist activity at alpha(2)-ARs and D-1 and D-2 receptors. Antagonism by S18327 of alpha(2)-ARs enhances adrenergic transmission and reinforces frontocortical dopaminergic transmission, whereas blockade of alpha(1)-ARs inhibits dorsal raphe-derived serotonergic pathways. As further described in the accompanying paper, this profile of activity may contribute to the potential antipsychotic properties of S18327.

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Documento generato il 28/11/20 alle ore 15:54:23