Heterocyclic antipsychotic drugs

S-Methylation is also an important pathway in the biotransformation of many sulfur-containing drugs. At least two separate enzymes, thiol methyltrans-ferase (TMT) and thiopurine methyltransferase (TPMT) are known to catalyze S-methylation in humans [87], TMT, a membrane-bound enzyme, catalyzes the S-methylation of captopril, D-penicillamine, and other aliphatic sulfhydryl compounds such as 2-mercaptoethanol. On the other hand TPMT, a cytosolic enzyme, catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds including 6-mercaptopurine and other thiopurines. Recently, S-methyltransferase has been shown to play a critical role in the metabolism of the antipsychotic drug, ziprasi-done, in humans [72, 88]. Both TPMT and TMT have been shown to be genetically polymorphic in humans. 

Amoxapine is a heterocyclic antidepressant. It is a metabolite of the antipsychotic drug, loxapine, and thus has the additional action of dopaminergic blockade. This action makes it a potentially useful therapy in depressed psychotic patients. 

At about the same time, the drug imipramine was first produced. It was originally developed as a phenothiazine (antipsychotic), but was found to have antidepressant properties. Soon came amitriptyline, followed later by other "tricyclic" and "heterocyclic" antidepressants. 

Just as in life, five-membered heterocycles are of utmost importance to drug discovery. The most conspicuous of all is probably atorvastatin (Lipitor), an HMG-CoA inhibitor. Another bioactive pyrrole shown below is an antipsychotic agent. 

A large number of unnatural molecules derived from these heterocycles are of great pharmaceutical importance, many of them being drug molecules currently in the market. Representative examples are shown in Figure 3.2, and include the antipsychotic haloperidol, the antidepressant paroxetine, the anti-HIV palinavir, the antihypertensive amlodipine, the cholesterol-lowering agent torcetrapib, and the mitosis inhibitor monastrol. 

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