Histamine-, norepinephrine-, and dopamine-sensitive central adenylate cyclases: effects of chlorpromazine derivatives and butaclamol.
A series of recently available derivatives (quaternary and hydroxylated) of chlorpromazine (CPZ) and butaclamol were evaluated with respect to antagonism of norepinephrine- (NE) (rat cerebral cortex), dopamine- (DA) (rat striatum) and histamine- (H) sensitive (rabbit cerebral cortex) adenylate cyclases. With incubated tissue slices (rat and rabbit cortices) CPZ-CH3, 7-OH-CPZ-CH3, beta-OH-CPZ and butaclamol displayed a capacity to inhibit either NE- or H- induced accumulation of adenosine cyclic 3',5'-monophosphate (cAMP). With the broken cellular enzyme responsive to DA, rather potent inhibition of enzyme activity (IC50 less than 24 micron) occurred with butaclamol, beta-OH-CPZ, 7,8,beta-triOH-CPZ, 7,8-dioxo-beta-OH-CPZ and 3,7,8-triOH-CPZ. It is concluded that the metabolites of CPZ contribute to the central therapeutic and/or side effects of the parent compound.
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002069:Butaclamol / Q000494:pharmacology*; D002746:Chlorpromazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003986:Dibenzocycloheptenes / Q000494:pharmacology*; D004298:Dopamine / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D006900:Hydroxylation; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D011817:Rabbits; D051381:Rats
D003986:Dibenzocycloheptenes; D006632:Histamine; D002069:Butaclamol; D000262:Adenylyl Cyclases; D002746:Chlorpromazine; D004298:Dopamine; D009638:Norepinephrine