Research Lines
I. DEVELOPMENT OF NEW CANDIDATES FOR DRUGS
In line with one of the goals of the Graduate in Pharmacology and Medicinal Chemistry Programme , this line of research developed in collaboration with several researchers of medicinal chemistry area is aimed at the preclinical characterization of new candidate drugs.
At the moment , we can highlight four projects:
I.1. Assessment of potential molecular mechanism of antipsychotic action of LASSBio -579 and N- fenilpiperazínicos new derivatives and piperazine N -substituted.
Schizophrenia is a severe chronic neuropsychiatric disorder that affects 1% of the world's population. Despite major investments in research attempts to develop effective antipsychotic drugs for the three levels of symptoms and with few adverse effects have been unsuccessful, probably due to the complexity of the disease, which still unclear etiology involve several types of receptors and different neurobiological circuits . The objective of this sub-project is to evaluate the affinity and intrinsic activity of the novel compounds N-fenilpiperazínicos and piperazine N-substituted derivatives LASSBio-579 compound (to produce blockade of the dopaminergic system in vivo, at doses that do not produce catalepsy) for different receptors or are potential targets for antipsychotic effect (D2, 5-HT2A and 5-HT1A receptors, D4 and 5-HT2C receptors, receptors and glutamate transporters) or are responsible for potential adverse effects (a1-adrenergic and muscarinic), with the aim of optimize this atypical antipsychotic compound-prototype as well as seeking alternative mechanisms such as the signaling pathways involving GSK3, using cellular model of human neuroblastoma.
I.2.Derivatives N- fenilpiperazínicos the search for new compounds prototypes for the treatment of Benign Prostatic Hyperplasia (BPH).
It is considered that chronic disease involving the alteration of cell signaling of more than one type of receptor and therefore, drugs that are targeted to act on more than one receptor subtype may be useful therapeutically. This concept is based on network models suggests that the partial inhibition of multiple targets can be more efficient than complete inhibition of a single target. It is estimated that about 50% of men aged over 50 have some symptoms of BPH. The ideal drug for the treatment of BPH should prevent or reverse possibly hyperplasia, prostatic and promote relaxation. Among the drugs approved for treatment of BPH, the adrenoceptor antagonists A1A / D have the best cost-benefit ratio for the patient. Thus, there is interest in developing drugs with higher affinity adrenoceptor A1D and A1a, A1b rather than. With the discovery of some G-protein coupled receptors (GPCRs), a1D adrenoceptor agonist and 5-HT1A receptor, stimulate prostatic cell proliferation, there is the possibility to evaluate the use of antagonists of these GPCRs as to its anti-proliferative effect. Based on the evidence summarized above, this concept could be applied to the treatment of BPH, aiming at three different targets: alpha1A-adrenoceptor / D and 5-HT1A receptors. Therefore, the purpose of this line is further pharmacological characterization of novel N-derivatives fenilpiperazínicos in search of new lead compound for the treatment of benign prostatic hyperplasia.
I.3. Pharmacological Evaluation of natural and semi -synthetic bufadienolídeos looking for functional prototypes with selectivity for Na + / K + -ATPase.
Vide II.2.
1.4. Valuation of derivatives Connection profiles N acilhidrazônicos to A1 and A2a Adenosine receptors
This project aims to : 1. assess the connection profile derived from N- acilhidrazônicos to A1 and A2a receptors of adenosine, seeking information on selectivity and intrinsic efficacy to contribute to the development of new compounds drug candidates ; 2. select derived N- acilhidrazônicos (screening) for testing in models where the molecular target would be the A2a receptor (such as inflammation, silicosis and neuropathic pain) ; 3 or A1 receptor (such as inflammation , analgesia and disease, neuroprotection) . Another goal is to help validate connection in silico models to adenosinergic receptors (the A2a receptor).
II. Na + / K + -ATPase : PHYSIOLOGICAL ROLE AND DRUG Modulation
The Na + / K + ATPase is an enzyme located in the plasma membrane of most eukaryotic cells and transports Na + and K + against its electrochemical gradients , with a vital role in cellular functions . The influence of physiological and pathological aspects of the enzyme is one of the study focuses this line of research from our laboratory have assessed the expression of the isoforms of the Na + / K + -ATPase in sexual dimorphism during ontogeny in experimental models of hypertension and cardiac hypertrophy as a model of denervation of vas deferens , as well as analysis of other type ATPase SERCA and PMCA and ryanodine receptors.
Among the projects currently developed include:
1. Study of new signaling function of the Na + / K + -ATPase
A new role for just over 10 years was discovered the Na + / K + -ATPase: connecting cardiotonic steroids (ECTs), classic inhibitors of ion transport function, with the enzyme is capable of triggering intracellular signaling cascades. This occurs through the interaction of Na + / K + -ATPase with Tyr-Src kinase activation and thus a number of protein kinases, with a range of cellular effects still unknown. Among the various sub-projects we evaluate the molecular mechanism bufadienolidos diuretic effect testing the internalization hypothesis of Na + / K + -ATPase in the proximal tubule, the effect of different endogenous bufadienolidos on the activity of the various isoforms of the Na + / K + -ATPase , and seek ECTs able to separate the two effects of bufadienolidos binding to Na + / K + -ATPase (inhibition pump vs. activation of the signaling pathway for protein-protein interactions) and thus establish the structural requirements to obtain candidates for drugs with functional selectivity.
2. Study of new inhibitors of the Na , K- ATPase
This design aims to assess pharmacologically different natural and semi -synthetic bufadienolídeos as well as semisynthetic derivatives of digoxin in the different isoforms of Na, K -ATPase as well as in cellular models designed to evaluate the effects on proliferation vs. cell apoptosis.
III. SCREENING PHARMACOLOGIC
This sector / service was created in response to a demand from drug development projects in which we participate ( Millennium Institute INCT ) to increase the visibility of the tests available within their collaborative networks created at the time , as well as be able to make provision drug screening service to interested companies. This project mainly based on binding assays , was formalized as one of ICB extension projects. Information on this service can be found on the website ( http://www.icb.ufrj.br/cgi/cgilua.exe/sys/start.htm?sid=132 ) where an updated portfolio of the tests can be viewed and downloaded.
