NNC-19-1228 and NNC 22-0031, novel neuroleptics with a "mesolimbic-selective" behavioral profile.
NNC 19-1228 [1-(3(6-methylenedioxyphenylcarbamoyloxy) propyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl) piperidine] and NNC 22-0031 [4-(6-fluoro-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 alpha 1-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 alpha 1-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.
Nielsen
E B
EB
Department of Behavioral Pharmacology, Health Care Discovery, Målov, Denmark. ebn@novo.dk
Hansen
J B
JB
Grłnvald
F C
FC
Swedberg
M D
MD
Scheideler
M
M
D000661:Amphetamine; D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects*; D052160:Benzothiazoles; D001583:Benzoxazoles / Q000378:metabolism / Q000494:pharmacology*; D002219:Carbamates / Q000378:metabolism / Q000494:pharmacology*; D002375:Catalepsy / Q000139:chemically induced; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008774:Methylphenidate; D051379:Mice; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects
D014150:Antipsychotic Agents; D052160:Benzothiazoles; D001583:Benzoxazoles; D002219:Carbamates; C106129:NNC 191228; D011954:Receptors, Dopamine; C106128:NNC 220031; D008774:Methylphenidate; D000661:Amphetamine