Antipsychotics

Some antipsychotics include inosine-similar structures.

Mizoribine is inosine-similar and inhibits IMP dehydrogenase to limit guanosine-derivative production. It is used as an immunosuppressant: PMID 10390602.

Ribavirin is inosine-similar and inhibits IMP dehydrogenase to limit guanosine-derivative production. It is used as an antiviral: PMID 15650220.

Inosine-similar antipsychotics may likewise inhibit IMP dehydrogenase to limit psychosis-causing guanosine-derivative production. (More on immune connections to psychiatry)

Some antipsychotics include xanthosine-identifying 2-oxo (O) groups.

Mycophenolate is xanthosine-similar and inhibits both IMP dehydrogenase and GMP synthase: PMID 612712. It is used as an immunosuppressant.

Xanthosine-similar antipsychotics all lack the 6-oxo group that may inhibit IMP dehydrogenase, but may inhibit GMP synthase: either would limit psychosis-causing guanosine-derivative production. 

Pimavanserin is an interesting antipsychotic, not predicted to act as an antipsychotic by dopamine theory, since it has no affinity at the dopamine receptors, but predicted to help in the unique clinical application of antipsychotic for Parkinson's disease.  In that clinical scenario, purine theory predicts excess guanosine with limited guanine, best treated by a PNP activator. Active site shared with other PNP activators is present in pimavanserin. Compared against risperidone and haloperidol, both known for causing Parkinsonism, pimavanserin reduces Parkinsonian reactions (PNP activation increases guanine). Like aripiprazole, expect IMPDH and GMP synthase inhibition, increasing antipsychotic efficacy when used with risperidone: apparently haloperidol inhibits IMPDH sufficiently that adding pimavanserin did not improve antipsychotic efficacy in this trial. PMID 22954754. IMG

Clozapine shares an apparent 2-amine group with a subgroup of what are often described as second-generation antipsychotics. Typically guanosine-defining, this group is shared among similar antipsychotics and may bind and block D2/D3 receptors from guanosine-derivative activation, reducing psychosis.

Triazolam is shown for purine orientation of the substituted 7-member-ring (more here).

Antipsychotic phenothiazines show reliably share a guanosine-identifying 2-amino group. 

Non-antipsychotic phenothiazine promethazine does not.

The dopamine hypothesis suggests that all antipsychotics should work in all circumstances. In practice, patients sometimes respond minimally to one antipsychotic and dramatically to another, not correlated with D2/D3 binding. 

Sorting antipsychotics by chemical structure and correlating with different proposed target enzymes explains the clinical reality of disparate response better than 

     a) the dopamine hypothesis or 

     b) the second/ third generation label (refers to the decades in which agents were approved)

The term antipsychotic is consistent with a shared goal of decreasing the effect of guanosine-derivatives on the D2/D3 receptors.

(More on antipsychotic active sites and conversion to lona-acting injectables)