Effect of structural analogs of butaclamol (a new antipsychotic drug) on striatal homovanillic acid and adenyl cyclase of olfactory tubercle in rats.
The 3-isopropyl (I), 3-cyclohexyl (II) and 3-phenyl (III) analogs of the new antipsychotic drug butaclamol, which contains a 3-tertiary butyl group, and their respective (+)-enantiomers, but not (-)-enantiomers, caused a dose related elevation of rat striatal homovanillic acid concentration, indicative of an increased dopamine (DA) turnover; droperidol also exhibited this activity. The order of activity of the (+)-enantiomers was (butaclamol) approximately II greater than I greater than III. A decrease in striatal DA was observed with (+)-I and (+)-III at the highest dose used, but not at one-half the dose. Each analog antagonized the DA-induced increase in adenyl cyclase (EC 4.6.1.1) activity of olfactory tubercle homogenates, the order of activity of the racemates (except for II) AND (+)-ENANTIOMERS BEING (BUTACLAMOL) APPROXIMATELY I greater than III greater than II. The (+)-enantiomers of butaclamol and analogs were two to four times more potent than their respective racemates, with (+)-butaclamol and (+)-I displaying activity generally equivalent to fluphenazine. The respective (-)-enantiomers were ineffective indicating a stereochemical specificity for DA-receptor blockade. Such analogs presented should be of value in elucidating dopaminergic mechansims.
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003986:Dibenzocycloheptenes / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004329:Droperidol / Q000494:pharmacology; D004347:Drug Interactions; D006719:Homovanillic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D009830:Olfactory Bulb / Q000187:drug effects* / Q000201:enzymology*; D010648:Phenylacetates / Q000378:metabolism*; D011807:Quinolizines / Q000494:pharmacology; D051381:Rats
D014150:Antipsychotic Agents; D003986:Dibenzocycloheptenes; D010648:Phenylacetates; D011807:Quinolizines; D000262:Adenylyl Cyclases; D004329:Droperidol; D004298:Dopamine; D006719:Homovanillic Acid