Modelos de QSAR aplicados à atividade antidepressiva de derivados de hexahidro-pirrolo-isoquinolina

Abstract

Depression is a common psychological disorder that affects millions of people worldwide. Its etiology has not yet been fully elucidated, but it is known that monoaminergic systems play a critical role and are currently the basis of the treatment. However, despite the number of antidepressants available, these medicines fail to treat a portion of the patients, are associated with some undesirable side effects, and cause clinical improvement only after weeks of treatment. Therefore, the search for new active compounds becomes relevant, both to broaden the therapeutic options and to provide a better understanding of the pathophysiology of the disease. In this sense, the dual inhibition of serotonin transporter (SERT) and histamine H3 receptor appears as an interesting alternative, because it assists in increasing the serotonin levels as well asin alleviating some cognitive symptoms. Thus, this work aims to develop quantitative relationships in four dimensions between the structure of hexahydro-pyrrolo-isoquinoline compounds and their respective inhibitory constants for H3 and SERT, in order to identify important structural characteristics for the biological activity of these compounds. The QSAR models for both receptorshave demonstrated satisfactory statistical parameters that assure their robustness and predictability (H3R: R² = 0.808, Q² = 0.736, r²m = 0.670 and R²p = 0.771; SERT: R² = 0.818, Q² = 0.710, r²m = 0.580 and R²p = 0.728), and pharmacophoric groups important for biological activity. The binding of the tested compounds to SERT was also evaluated by docking the most active compound to the transporter binding site, where it was possible to suggest the existence of important intermolecular interactions. Therefore, together, this information can be used to guide the development of new bioactive molecules for the treatment of depression.