NNC-19-1228 AND NNC-22-0031, NOVEL NEUROLEPTICS WITH A MESOLIMBIC-SELECTIVE BEHAVIORAL PROFILE

NNC 19-1228 rbamoyloxy)propyl)-4-(6-flouro-1,2-benzisoxazol-3- yl)pipe ridine] and NNC 22-0031 ethylenedioxyphenylcarbamoyloxy)propyl)piperid ine] are newly developed compounds with an in vitro pharmacologic prof ile similar to that of clozapine, i.e., mixed dopamine (DA), 5-hydroxy tryptamine (5-HT)(2) and alpha(1)-adrenergic antagonist action. In pha rmacological experiments in mice, the compounds inhibited DA D-2 recep tor binding in vivo at doses that produced only moderate antagonism of methylphenidate (MPD)-induced stereotyped gnawing. However, the compo unds were markedly more potent in blocking MPD-induced motility, a mod el which showed a high degree of sensitivity to alpha(1)-adrenergic an tagonism, but not 5-HT2 antagonism. In rats, the NNC-compounds blocked conditioned avoidance responding and attenuated the discriminative st imulus effects of amphetamine, but failed to induce catalepsy. These r esults are discussed in terms of adrenergic, serotonergic and dopamine rgic interactions which suggest that the NNC compounds may act as DA a ntagonists with mesolimbic selectivity, and thus may have efficacy as antipsychotics without coincident extrapyramidal side effects.