Figure 12.10 • Major metabolic pathway for aripiprazole.
Ziprasidone. Ziprasidone (Geodon, a benzisothia-zolpiprazinylindolone derivative) also has the structural features of a hybrid molecule between a butyrophenone antipsychotic and a trazodone-like antidepressant. It is highly metabolized to four major metabolites, only one of which, S-methyldihydroziprasidone, likely contributes to its clinical activity (see Fig. 12.9). In humans, less than 5% of the dose is excreted unchanged. Reduction by aldehyde oxidase accounts for about 66% of ziprasidone metabolism; two oxidative pathways involving hepatic CYP3A4 account for the remainder.
Aripiprazole. Aripiprazole (Abilify). The newest, long-acting aripiprazole (an arylpiperazine quinolinone derivative), appears to be partial agonist of D2 receptors (i.e., it stimulates certain D2 receptors while blocking others depending on their locations in the brain and the concentration of drug). Bioavailability of aripiprazole is around 87%, with peak plasma concentration attained at 3 to 5 hours after dosing. It is metabolized by dehydrogenation (see Fig. 12.10), oxidative hydroxylation, and n-dealkylation, largely mediated by hepatic CYPs 3A4 and 2D6.
The diphenylbutylpiperidine class can be considered a modification of the fluorobutyrophenone class. Because of their high lipophilicity, the compounds are inherently long acting. Pimozide has been approved for antipsychotic use, and penfluridol has undergone clinical trials in the United States. Overall, side effects for the two compounds resemble those produced by the fluorobutyrophenones.
Several jS-aminoketones have been examined as antipsychotics.31 They evolved out of research on the alkaloid lobeline. The overall structural features associated with activity
can be seen in the structure of molindone. In addition to the j-aminoketone group, there must be an aryl group positioned as in molindone. It might be conjectured that the proton on the protonated amino group in these compounds H-bonds with the electrons of the carbonyl oxygen atom. This would produce a cationic center, two-atom distance, and an aryl group that could be superimposed on the analogous features of protonated DA.
Molindone Hydrochloride. Molindone hydrochloride, 3-ethyl-6,7-dihydro-2-methyl-5-morpholinomethyl)indole-4(5#)-one monohydrochloride (Moban), is about as potent an antipsychotic as trifluoperazine. Overall, side effects resemble those of the phenothiazines.
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