NNC 19-1228 and NNC 22-0031, novel neuroleptics with a “mesolimbic-selective” behavioral profile |
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Authors: | E B Nielsen John Bondo Hansen Frederik C Grønvald Michael D B Swedberg Mark Scheideler |
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Institution: | Department of Behavioral Pharmacology, Health Care Discovery, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 M?lov, Denmark FAX (+45) 44/66 2980, e-mail: ebn@novo.dk, DK Department of Medicinal Chemistry, Health Care Discovery, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 M?lov, Denmark, DK Department of Molecular Pharmacology, Health Care Discovery, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 M?lov, Denmark, DK
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Abstract: | NNC 19-1228 1-(3(6-benzothiazolylcarbamoyloxy)propyl)-4-(6-flouro-1,2-benzisoxazol-3-yl)piperidine] and NNC 22-0031 4-(6-flouro-1,2-benzisoxazol-3-yl)-1-(3-(3,4-methylenedioxyphenylcarbamoyloxy)propyl)piperidine]
are newly developed compounds with an in vitro pharmacologic profile similar to that of clozapine, i.e., mixed dopamine (DA),
5-hydroxytryptamine (5-HT)2 and α1-adrenergic antagonist action. In pharmacological experiments in mice, the compounds inhibited DA D2 receptor binding in vivo at doses that produced only moderate antagonism of methylphenidate (MPD)-induced stereotyped gnawing.
However, the compounds were markedly more potent in blocking MPD-induced motility, a model which showed a high degree of sensitivity
to α1-adrenergic antagonism, but not 5-HT2 antagonism. In rats, the NNC-compounds blocked conditioned avoidance responding and attenuated the discriminative stimulus
effects of amphetamine, but failed to induce catalepsy. These results are discussed in terms of adrenergic, serotonergic and
dopaminergic interactions which suggest that the NNC compounds may act as DA antagonists with mesolimbic selectivity, and
thus may have efficacy as antipsychotics without coincident extrapyramidal side effects.
Received: 16 May 1996/ Final version: 14 August 1996 |
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Keywords: | NNC 19-1228 NNC 22-0031 Dopamine Neuroleptic Behavioral models Rat |
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