Contribution to antidepressive drug development

• Grant number: 13/18897-7
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2014
• End date: February 28, 2017
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Lanfranco Ranieri Paolo Troncone
• Grantee: Lanfranco Ranieri Paolo Troncone
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated researchers: Cristoforo Scavone ; João Paulo dos Santos Fernandes

Abstract

Depression is an incapacitating and hardly treated psychiatric condition so the development of new drugs has been a priority for big pharmaceutical companies and academics. This project is aimed at investigating the neurochemical profile of several new molecular entities (arylsulphonyltriptamines, quinazolines and benzo dihydrofuranes), some with preliminary anti-depressant data already gathered but many without defined profile, that have been obtained by three associate collaborators, two of them from the Virginia Commonwealth University (VCU) and one from Universidade Federal de São Paulo (UNIFESP-Diadema). Primary investigation involve the effects on serotonin uptake and release by rat frontal cortical tissue in vitro and binding on 5HT2c, 5HT3 and 5HT6 as well as histamine receptors using recombinant cell membranes. Traditional behavioral tests will be performed as the Porsolt's forced swimming test in rats for a preliminary or complementary evaluation. As behavioral testing of anti-depressants has been reputed as a poor predictor of human anti-depressive activity, we will also investigate the anedonia model (sucrose preference) induced by unpredictable continuous mild stress (UCMS), proposed as one of the most reliable models. According to this model, UCMS leads to a state of anedonia, a common feature of major depression which is reverted by prolonged anti-depressive treatments. It is, though, important to notice that many groups report failure of this procedure in inducing anedonia and according to our review of the literature, one specific aspect has been systematically neglected that is the proper nature of the stresses employed to induce anedonia, i.e., a physical or processive stress, which have been consider to rely on very different neural circuits. Together with a brain mapping of neural activity in normal and anedonic rats, compared to depressive human brain mapping may yield clues to the understanding of depression from a neural circuit standpoint. The elucidation of these aspects may lead to the proposition of a perfected and more reliable pre-clinical test for antidepressants, this meaning an important issue in the process of developing new therapeutic agents. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

RAMOS, ADRIANA T.; TUFIK, SERGIO; TRONCONE, LANFRANCO R. P.. Control of Stress-Induced ACTH Secretion by Vasopressin and CRH: Additional Evidence. NEUROPSYCHOBIOLOGY, v. 73, n. 3, p. 184-190, 2016. (15/08098-5, 98/14303-3, 13/18897-7)

CORREA, MICHELLE FIDELIS; VARELA, MARINA THEMOTEO; BALBINO, ALEKSANDRO MARTINS; TORRECILHAS, ANA CLAUDIA; LANDGRAF, RICHARDT GAMA; PAOLO TRONCONE, LANFRANCO RANIERI; DOS SANTOS FERNANDES, JOAO PAULO. 1-[(2,3-Dihydro-1-benzofuran-2-yl) methyl]piperazines as novel anti-inflammatory compounds: Synthesis and evaluation on H3R/H4R. CHEMICAL BIOLOGY & DRUG DESIGN, v. 90, n. 2, p. 317-322, AUG 2017. (13/20479-9, 13/18897-7, 14/16564-3)