Acetophenazine Maleate

Finding good drug leads de novo from large chemical libraries, real or virtual, is not an easy task. High-throughput screening is often plagued by low hit rates and many leads that are toxic or exhibit poor bioavailability. Exploiting the secondary activity of marketed drugs, on the other hand, may help in generating drug leads that can be optimized for the observed side-effect target, while maintaining acceptable bioavailability and toxicity profiles. Here, we describe an efficient computational methodology to discover leads to a protein target from safe marketed drugs. We applied an in silico “drug repurposing” procedure for identification of nonsteroidal antagonists against the human androgen receptor (AR), using multiple predicted models of an antagonist-bound receptor. The library of marketed oral drugs was then docked into the best-performing models, and the 11 selected compounds with the highest docking score were tested in vitro for AR binding and antagonism of dihydrotestosterone-induced AR transactivation. The phenothiazine derivatives acetophenazine, fluphenazine, and periciazine, used clinically as antipsychotic drugs, were identified as weak AR antagonists. This in vitro biological activity correlated well with endocrine side effects observed in individuals taking these medications. Further computational optimization of phenothiazines, combined with in vitro screening, led to the identification of a nonsteroidal antiandrogen with improved AR antagonism and marked reduction in affinity for dopaminergic and serotonergic receptors that are the primary target of phenothiazine antipsychotics.

The affinity of selected antipsychotic and antidepressant drugs for the muscarinic receptor was studied in membranes from both human and rat striatum and cerebral cortex. While there are regional differences in the anticholinergic potency of the drugs, there is good agreement between the obtained inhibition constants from the corresponding human and rat striatum (r: 0.98) and from human and rat cerebral cortex (r: 0.96). There is also good agreement between the obtained Ki values within one species: human cerebral cortex versus human striatum (r: 0.99) and for rat cerebral cortex and rat striatum (r: 0.87). Thus, the previously published quantitative estimates of the antimuscarinic activity of psychoactive drugs which were derived from studies on membranes from rat brain give an accurate estimate of the antimuscarinic activity in human brain. The drugs tested in this study include chlorpromazine acetophenazine, haloperidol, sulpiride, remoxipride (FLA-731 (-), a substituted benzamide), amitriptyline and two serotonin uptake blockers: norzimelidine and alaproclate.