Synthesis of Fused Triazolo-Pyridobenzodiazepine Analogs for Use as Potential Atypical Antipsychotic Treatments in Schizophrenia.

摘要

Schizophrenia is a chronic mental illness that displays a wide variety of psychological symptoms and affects millions of people worldwide. It has a very complicated etiology, some of which is still not understood, but the altered activity of both dopamine and serotonin receptors have been implicated in the cause of this disease. Antipsychotics (APDs) developed over the years have split into two distinct categories: classical and atypical. Classical APDs target the dopamine receptors and are known to produce serious extrapyramidal side effects. There is a large percent of patients who are treatment-resistant to these drugs, which has aided in the development of atypical APDs. These compounds mainly target serotonin receptors, and tend to have very high affinity for the 5-HT2A receptor. Though atypical APDs currently on the market show reduced levels of extrapyramidal side effects, they are not without their own problems.;JL 13 is a benzoxazepine derivative with an atypical profile that has been shown to reduce extrapyramidal side effects consistent with atypical APDs. Based on its core structure, previous efforts were made to design and synthesize a large library of fused triazole derivatives of both benzoxazepine and benzodiazepine molecules. None of these analogs showed any significant binding affinity to the 5-HT2A serotonin receptor, thus reevaluation of compound structure was crucial. The relationship between the direction of the substituent attached to the triazole ring and its binding ability then came into question. Presented herein is a new synthetic route that was designed to create fused triazolo-analogs in which the direction of the substituent was reversed in an attempt to improve binding affinity.