Antidepressants and anxiolyitic design trends

Abstract

Depression constitutes an international health problem. It is estimated that 320 million people worldwide are clinically depressed. Effective antidepressant treatments have been available for more than 40 years. Although modern antidepressants lack many of the side-effects and toxicity of the first generation tricyclics and monoamine oxidase inhibitors, their efficiency has not been substantially improved comparing to older agents. Unfortunately, the modern drug discovery technologies of combinatorial chemistry and throughput screening are based on relatively simple in vitro assays and lack pre-clinical model of depression make this research difficult. Most antidepressants require additional time to achieve therapeutic effects and there is a certain population of patients resistant to current therapies which means that etiology of depression is too complex. Coming research should clarify true depression mechanism and identify new targets of the third antidepressants generation. Anxiety is a normal emotion and essential part of response to stressful and threatening stimuli. At present, a numerous drugs with various mechanism of action are available for pharmacoterapy of anxiety disorders. The benzodiazepines represent the most important drugs in the treatment of anxiety. In addition to their anxiolytic properties, benzodiazepines possess sedative, hypnotic, anticonvulsant and other effects but side effects also-upon prolonged administration they produce withdrawal symptoms and dependency. Research has shown that cholecystokinin and corticotrophin-releasing factor are important neurotransmiters and may have role in the mediation of anxiety. Neuropeptide Y has shown an anxiolytic effect in several animal models. CCK, CRF and neuropeptid Y receptor agonists and antagonists are targets of new anxiolitic drugs.

Anksioznost je normalna emocionalna reakcija na preteći ili stresni stimulans. U farmakoterapiji ove bolesti koristi se veliki broj lekova različitog mehanizma delovanja od kojih su benzodiazepini najvažniji. Benzodiazepini, pored anksiolitičkog poseduju sedativni, hipnotički, antikonvulzivni i druge efekte ali posle duže upotrebe razvija se tolerancija, dovode do zavisnosti i često su predmet zloupotrebe. Novija istraživanja su pokazala da, pored serotonina i noradrenalina i drugi neurotransmiteri kao što su holecistokinin (CCK) i oslobađajući faktor za kortikotropin (CRF) imaju značajnu ulogu u anksioznosti. Neuropeptid Y (NPY) takođe pokazuje anksiolitički efekat na životinjama. Agonisti i antagonisti receptora holecistokinina, oslobađajućeg faktora za kortikotropin i neuropeptida Y su cilj sinteze novih anksiolitika.