Dissertações em Química Medicinal e Modelagem Molecular (Mestrado) - PPGQMMM/ICS

URI Permanente para esta coleçãohttps://repositorio.ufpa.br/handle/2011/14431

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Modelo experimental para indução de hemiparkinsonismo por 6-hidroxidopamina em primatas sapajus apella e avaliação das alterações motoras
(Universidade Federal do Pará, 2019-06-09) LEAL, Leon Claudio Pinheiro; KREJČOVÁ, Lane Viana; http://lattes.cnpq.br/2604693973864638; https://orcid.org/0000-0001-8016-5283; BAHIA, Carlomagno Pacheco; http://lattes.cnpq.br/0910507988777644; https://orcid.org/0000-0003-3794-4710
Parkinson's disease is currently the second most common neurodegenerative disease in the world, with a high incidence in North and South America and Europe, for more than 50 years we have not seen any revolutionary treatment for the disease and many aspects of its neuropathology that still remain without a concrete enlightenment, in this feeling the experimental model in primates approaches the human reality are invaluable value for the development of new therapies and elucidation on mechanisms related to the disease. The 6-hydroxydopamine model in primates is a model that mimics some motor symptoms characteristic of PD. The present study aimed to develop a protocol for the induction of HemiParkinsonism in Sapajus apella primates. Three Sapajus Apella monkeys, all adult males, were submitted to daily conditioning sessions using the positive reinforcement clicker technique for primate chair positioning. Concurrently, the staircase and Brinkman tray motor tests were performed to determine laterality by the manual preference and dominance attributes. After this period, two 6-OHDA induction protocols were performed, the first protocol was injected into 10 sites in the nucleus striatum and the second protocol was injected into 10 sites in the nigrostriatal pathways, one week after the injections were performed twelve weeks of clinical analysis . All animals learned the input and positioning behaviors in the chair in a minimum of 30 sessions using pure positive reinforcement. The results of the staircase test demonstrated that the animals presented laterality consistent with the assignments of manual preference and dominance. The Brinkman test, specifically, presented lower sensitivity for determination of the same attributes, despite being the most commonly used test. Clinical analysis revealed that the second induction protocol had more motor symptoms characteristic of PD. Induction by 6-OHDA in the nigrostriatal pathways has been shown to be a good induction method for treatment studies and for a better understanding of the disease.
Acesso aberto (Open Access)
Planejamento e desenvolvimento de derivados do muscimol com propriedades antioxidantes
(Universidade Federal do Pará, 2019-12-09) SOUSA, Alanna Crystine Lima Farias de; BORGES, Rosivaldo dos Santos; http://lattes.cnpq.br/4783661132100859; https://orcid.org/0000-0003-4072-7573
Muscimole is a psychoactive izoxazole compound extracted from mushrooms of the genus Amanita muscaria has been studied as a GABA inhibitor due to behavioral genes, since its structural structure is based on mammalian neurotransmitters GABA and glutamic acid. Due to its high selectivity and its own potential for neural activity, it is able to act as a drug, since it has a higher affinity for the GABAA receptor than GABA. Since the 1980s studies suggesting that GABA and muscimol are related to serotonin concentration, where increased GABA concentration or muscimol injection increases serotonin concentration and decreases inactive product after serotonin. oxidation, 5-HIAA. For this reason, this work aimed to plan and develop muscimol derivatives as an alternative for increase the serotonin using antioxidant activity. For this reason, this work aimed to plan and develop muscimole derivatives as an alternative for the treatment of anxiety and depression. For this, was used the drug planning method known as bioisosterism, which is characterized by being compounds or subunits of bioactive substances with similar structural characteristics, as well as similar physical and chemical properties with the ability to present analogous biological properties, can be agonists or antagonists. Firstly, a study was made of the groups that are responsible for the biological activity through the muscimole pharmacophores, where the groups that interact with the GABAA receptor are the -NH2 groupings, the isoxazole ring, as well as the oxygen present in the carbonyl. Then molecular modeling was performed, which was performed using the DFT B3LYP 6-311G (2d, 2p) method to verify the values of HOMO, LUMO, GAP, ionization potential (IP), bond energy dissociation, hydrogen atom transfer and single electron transfer, where it was found that the derivative S1 presented values equal -7.61 eV, -1.36 eV, -6.25 eV, 205.87.85 kcal/mol, 80.81 kcal/mol, -15.45 kcal/mol e -6.99 kcal/mol, respectively. The derivative S2 presented values of -6.80 eV, -1.08 eV, 5.72 eV, 198.41 kcal/mol, 77.73 kcal/mol, -18.53 kcal/mol e -0.47 kcal/mol, respectively. When compared with GABA, it was found that they are reactive, among which derivative S2 is more reactive, presenting lower GAP value compared to S1, and with PI values, it was found that derivative S1 has a lower electron donor capacity than derivative S2, highlighting that the best route is through the hydrogen donation mechanism. Then, the regioisomers derivatives were synthesized with a yield for S1 and S2 of 74,08% and 60,42%, respectively, as well as characterization through the melting point, where the derivative S1 had equal melting point. at 114,5 ° C - 115 ° C and S2, 182,5 ° C, showing that the synthesized molecules are pure, since they were compared with the data in the literature. With these data it is possible to say that muscimol derivatives have high antioxidant activity.

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