Neurochemical study of mafoprazine, a new phenylpiperazine derivative.
Mafoprazine, a phenylpiperazine derivative, was neurochemically investigated in rats to determine its action mechanism. The rank order of affinity of mafoprazine for neuronal receptors was D2 greater than or equal to alpha 1 greater than S2 greater than alpha 2 much greater than D1 greater than beta greater than mACh. The affinity of mafoprazine for D2 receptors (Ki = 10.7 nM) was 2 times higher than that of azaperone, and 6 and 16 times lower than those of chlorpromazine and haloperidol, respectively, whereas the D2 receptor selectivity [D1/D2 (Ki value ratio)] of mafoprazine was 10, 9 and 2 times higher than those of chlorpromazine, azaperone and haloperidol, respectively. The affinity of mafoprazine for alpha 2 receptors in terms of the ratio of the Ki values for D2 and alpha 2 receptors (D2/alpha 2) was 345, 26 and 3 times higher than those of haloperidol, chlorpromazine and azaperone, respectively. Mafoprazine slightly showed the inhibitory effect on dopamine-stimulated adenylate cyclase (IC50 = 52300 nM), and it had almost no affinity for beta and mACh receptors. Mafoprazine significantly increased dopamine metabolites in the corpus striatum and nucleus accumbens, although to lesser extents as compared with azaperone and chlorpromazine. These results suggest that mafoprazine probably manifests its antipsychotic action mainly through D2 receptor blocking activity and alpha-adrenergic activity (alpha 1 receptor blocking activity and alpha 2 receptor stimulating activity).
Fukuchi
I
I
Pharmacology Department, Safety Research Laboratory, Tanabe Seiyaku Co., Ltd., Osaka, Japan.
Kawashima
K
K
Matsuoka
Y
Y
Ishida
R
R
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001679:Biogenic Amines / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002746:Chlorpromazine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology; D007202:Indicators and Reagents; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism
D001679:Biogenic Amines; D007202:Indicators and Reagents; D010879:Piperazines; D011954:Receptors, Dopamine; D011955:Receptors, Drug; C057002:mafoprazine; D000262:Adenylyl Cyclases; D002746:Chlorpromazine; D004298:Dopamine