Anti-apomorphine effects of phenothiazine drug metabolites.
The potencies in producing muscle relaxation, and in antagonizing apomorphine-induced climbing and hypothermia in mice, were examined for chlorpromazine, levomepromazine and their main metabolites, and for fluphenazine and 7-hydroxy fluphenazine. 3-Hydroxy chlorpromazine was more potent than chlorpromazine in antagonizing apomorphine-induced climbing, while levomepromazine and 3-hydroxy levomepromazine were equipotent in this test. The 3-hydroxy metabolites of chlorpromazine and levomepromazine were more potent than the parent compounds in antagonizing hypothermia, and had significantly weaker muscle relaxant effects than the parent compounds. The 7-hydroxy and N-monodesmethyl metabolites were generally less potent that the parent compounds in antagonizing apomorphine-induced effects. N-Monodesmethyl levomepromazine had a pronounced muscle relaxant effect, like levomepromazine itself. The sulphoxide metabolites of chlorpromazine and levomepromazine were inactive in all tests. Their potencies in these tests indicate that among the metabolites 7-hydroxy chlorpromazine, N-monodesmethyl chlorpromazine and 3-hydroxy levomepromazine, which have all been identified in plasma from patients, may contribute to the antipsychotic effects of the drugs, and furthermore that N-monodesmethyl levomepromazine may contribute to the sedative effects of levomepromazine.
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000037:antagonists & inhibitors*; D001831:Body Temperature / Q000187:drug effects; D005476:Fluphenazine / Q000494:pharmacology; D008297:Male; D008728:Methotrimeprazine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects
D014150:Antipsychotic Agents; C044467:N-desmethyllevomepromazine; D008728:Methotrimeprazine; D001058:Apomorphine; D005476:Fluphenazine