Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2017-04-18T16:13:54Z No. of bitstreams: 1 AldoFonsecaDeSouza_DISSERT.pdf: 4744704 bytes, checksum: ea072ae471453a5d19b76eba7406e2a3 (MD5) / Approved for entry into archive by Monica Paiva (monicalpaiva@hotmail.com) on 2017-04-18T16:23:57Z (GMT) No. of bitstreams: 1 AldoFonsecaDeSouza_DISSERT.pdf: 4744704 bytes, checksum: ea072ae471453a5d19b76eba7406e2a3 (MD5) / Made available in DSpace on 2017-04-18T16:23:57Z (GMT). No. of bitstreams: 1 AldoFonsecaDeSouza_DISSERT.pdf: 4744704 bytes, checksum: ea072ae471453a5d19b76eba7406e2a3 (MD5) Previous issue date: 2015-08-28 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES) / A ansiedade, embora conceituada como um sentimento vago e desagrad?vel de medo e apreens?o derivados de antecipa??o de perigo de algo desconhecido ou estranho, ? tamb?m caracterizada como um estado emocional de grande valor adaptativo. Dentre os sistemas de neurotransmiss?o envolvidos na express?o de comportamentos relacionados ? ansiedade, o sistema serotonin?rgico tem sido amplamente estudado. Considerando a presen?a do receptor de serotonina do tipo 7 (5-HT7) na por??o dorsal da subst?ncia cinzenta periaquedutal (DPAG), uma estrutura bastante implicada nos comportamentos defensivos, o presente estudo verificou se a manipula??o farmacol?gica do receptor 5-HT7 alteraria as respostas comportamentais relacionadas ? ansiedade em ratos. Ratos Wistar (90?5 dias) foram submetidos a dois protocolos experimentais. No experimento 1, ratos submetidos ? cirurgia estereot?xica para implante de c?nula-guia receberam a administra??o intra-DPAG de ve?culo (Salina + DMSO) ou do agonista de receptores 5-HT7 AS19 nas doses de 0,05, 0,1 e 0,2 ?g. Cinco minutos ap?s a administra??o, os animais foram testados no labirinto em cruz elevado (LCE). Vinte e quatro horas depois, estes mesmos animais passaram pelo teste do campo aberto. J? no experimento 2, os animais receberam a infus?o do antagonista de receptor 5-HT7 SB 269970 (5, 10 ou 20 nmols) ou ve?culo seguida de administra??o intra-DPAG do agonista AS19 (0,1 ?g) ou ve?culo previamente aos testes comportamentais. Os resultados mostraram que, quando administrado isoladamente, o agonista AS19 na dose de 0,1 ?g, mas n?o nas doses de 0,05 e 0,2 ?g, diminuiu a porcentagem de entradas e tempo gasto nos bra?os abertos do LCE, sugerindo efeito do tipo ansiog?nico. A administra??o intra-DPAG do antagonista SB 269970 na dose de 10 nmols promoveu efeito do tipo ansiol?tico, quando observado o aumento na porcentagem de tempo gasto nos bra?os abertos do LCE. Este efeito foi revertido pela administra??o do agonista AS19 na dose de 0,1 ?g. Nenhuma das drogas testadas alterou par?metros de locomo??o analisados no teste do campo aberto, sugerindo que os efeitos relacionados ? ansiedade n?o estejam associados a altera??es na locomo??o dos animais. Os dados aqui obtidos permitem a conclus?o de que receptores do tipo 5-HT7 da DPAG, quando ativados, modulam um efeito do tipo ansiog?nico. Ainda, o bloqueio de receptores 5-HT7 nesta ?rea favorece um efeito do tipo ansiol?tico, que vem sendo descrito na literatura ap?s a administra??o perif?rica de antagonistas destes receptores.

Drug discovery contains many strategies, one of which is the privileged scaffold strategy. This strategy incorporates a similar molecular framework within a collection of drug-like compounds in order to target various receptors. These scaffolds are useful to drug discovery scientists since they assist in developing libraries as well as demonstrating selectivity to a target. Oxazolidinones are 5-membered heterocyclic compound containing an oxygen, a nitrogen, and a carbonyl within the ring system. In this present study, the oxazolidinone structure was utilized as a privileged scaffold to target serotonin receptor 7 (5-HT7), mutated BRAF kinase (BRAFV6000E), Bruton’s tyrosine kinase (BTK), and Cyclin-dependent protein kinase 4 and 6 (CDK4/6). Aryl piperazines and piperidines were integrated as another privileged scaffold to support the selectivity towards 5-HT7, while aminopyrimidines were employed to increase binding against the kinases. The 5-HT7 oxazolidinone series was successfully synthesized and analyzed against 5-HT7; however, the three kinase oxazolidinone series were not successfully synthesized.Candidemia is the most common bloodstream infection in the U.S. and is associated with high patient mortality rates. Due to prolonged and/or repeated clinical use of current antifungal agents, drug-resistant fungi have become an emerging problem. There is a need for new antifungals to assist in overcoming drug resistant fungi. In the second project outlined in this work, a series of ketoconazole analogs were designed and successfully synthesized. The ketoconazole analogs exhibited antifungal activity; however, no clear trends were observed in this series. Overall, the series exhibited less CYP3A4 inhibition than the parent compound, ketoconazole. / Pharmaceutical Sciences

No description available.

Inflammatory bowel disease (IBD) is a serious, complex disease that is challenging to treat effectively and affects over 5 million people globally. Current treatment goals for both subtypes of IBD, Ulcerative Colitis (UC) and Crohn Disease (CD), focus on attaining and maintaining remission through anti-inflammatory agents, immunomodulators, or biologics. In spite of these treatments, more than 25% of patients require devastating surgical removal of part of their colon due to severe inflammation. Recent advances in our understanding of serotonergic effects beyond the central nervous system (CNS) provide encouragement for IBD treatment. The newest member of serotonin receptor family, the 5-HT7 subtype, is involved in the release of pro-inflammatory cytokines following stimulation by serotonin in the gastrointestinal tract (GIT). Khan et al have shown that inflammation associated with the DSS and DNBS mouse models of IBD is significantly attenuated in knock-out mice lacking the 5-HT7 receptor or mice treated with 5-HT7 selective antagonists. Previously reported 5-HT7 receptor antagonists (e.g., SB-269970) readily crosses the blood brain barrier (BBB) and are therefore not good choices for IBD treatments. Our group has identified a novel series of arylpiperazinyl lactones with high affinity and excellent selectivity for the 5-HT7. The aim of this project is to design, synthesize, and characterize new gamma-butyrolactone-based 5-HT7 ligands with high affinity, good selectively, acceptable drug-like properties, with limited access to the CNS. A total of 18 compounds were successfully synthesized and evaluated as potential new lead compounds for the treatment of IBD. / Pharmaceutical Sciences

No

Yes / Rationale: 5-HT receptor mechanisms have been suggested to mediate improvements in cognition in schizophrenia. Aim: To investigate the involvement of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in female rats, a task of relevance to schizophrenia. Methods: Adult female hooded-Lister rats were trained to perform an operant reversal learning task and then received sub-chronic PCP (2 mg/kg) or vehicle i.p. twice daily for seven days, followed by 7-days washout. Rats then received an acute dose of the 5-HT7 receptor antagonist SB-269970A (1.0, 3.0, 10.0 mg/kg; i.p.) or vehicle. In experiment 2, PCP-treated rats received the selective 5-HT2C receptor antagonist, SB-243213A acutely (1.0, 3.0, 10.0 mg/kg; i.p.) or vehicle. In experiment 3, PCP-treated rats received the 5-HT1A receptor partial agonist, buspirone (0.15625, 0.3125, 0.625 mg/kg, i.p.) in combination with the selective 5-HT1A receptor antagonist WAY-100635 (0.3, 1.0 mg/kg). Results: In all experiments sub-chronic PCP significantly impaired reversal phase performance (P<0.01-0.001), with no effect in the initial phase. SB-269970A at 3.0 and 10.0 mg/kg significantly improved the PCP-induced deficit (P<0.05). SB-243213A also significantly attenuated the deficit at 10 mg/kg (P<0.05). In experiment 3, buspirone attenuated the deficit with significant effects at 0.3125 mg/kg and 0.625 mg/kg (P<0.05). WAY-100635 at 0.3 and 1.0 mg/kg produced a partial attenuation of buspirone’s effect as buspirone (0.3125 mg/kg) in the presence of WAY-100635 did not significantly reverse the PCP-induced deficit. Conclusions: These studies implicate the role of 5-HT7, 5-HT2C and 5-HT1A receptors in the improvement of cognitive dysfunction of relevance to schizophrenia.

Of the seven existing classes of serotonin receptors, the 5-HT7 receptors (5-HT7Rs) are the most recently discovered. Abundance of 5-HT7 in the central nervous system is suggestive of the receptor’s role in several physiological and pathophysiological functions. Existing research has afforded a number of compounds exhibiting specific affinity to the receptor. These selective ligands can provide structural information about the receptor and can serve as the foundation for pharmacological profiling . This thesis describes the synthesis of substituted pyrimidines and pyridines for affinity to the 5-HT7 receptor. Organometallic species are the cornerstone for sev-eral of the synthetic pathways.

No description available.

Parmi tous les neurotransmetteurs identifiés à ce jour, la sérotonine (5-hydroxytryptamine, 5-HT) est impliquée dans le système le plus complexe de récepteurs. Parmi eux, les récepteurs 5-HT7 qui sont les derniers découverts (1993) semblent avoir des implications multiples tant au niveau central que périphérique. Le potentiel thérapeutique représenté par la découverte de ligands 5-HT7 sélectifs vis-à-vis d'autres RCPGs a motivé notre projet de recherche. Nos études sont orientées vers la conception de trois classes distinctes de ligands. Une première famille à été conçue sur une charpente benzimidazolone. Diverses pharmacomodulations ont permis un changement du profil d'activité de 5-HT1A vers 5-HT7. Une deuxième famille de composés à structure furo- ou pyrano[2,3-b] pyridinique constitue des analogues azotés d'un des plus intéressants agonistes sélectifs 5-HT7 actuels. La synthèse de ces dérivés a été conduite via la mise en oeuvre d'une étape clé de cycloaddition intramoléculaire de Diels-Alder à partir de 1,2,4-triazines judicieusement fonctionnalisées en 3 par une chaine aminoalkynol. Cette méthodologie nous a permis de faire varier les substituants alkyle de l'amine, la nature et la position du motif aryle sur le noyau pyridinique, ainsi que la taille du cycle non-aromatique. La synthèse d'une dernière famille de dérivés bisaryliques a enrichi les études de relation structure-activité, connues dans la littérature, associées à ce type de ligands 5-HT7. La variation du cycle aromatique central (phényle, 1,3-diazine et 1,2,4- triazine) a révélé d'importantes conséquences sur l'affinité des molécules.

Una de las principales cuestiones en farmacología molecular de los GPCR es entender los mecanismos estructurales de las siete hélices transmembrana (TM) que se producen para estabilizar ya sea Rg o los diferentes estados R*. Para entender el mecanismo que cambia el equilibrio del conjunto a un estado activo R* se construyeron tres de los receptores de la serotonina (5-HT4, 5-HT6, y 5 HT7) sobre la base de su información más reciente de cristalografía de rayos X. Dando lugar a dos modelos de cada receptor: una inactiva y otra activa. Los modelos, mejorados y evaluados con la ayuda de datos farmacológicos y químicos se utilizaron principalmente para comprender la interacción entre un ligando y su receptor y su mecanismo de acción. Estos hallazgos estructurales pueden a su vez resultar útiles para el diseño de nuevos fármacos más eficaces y selectivos. / One of the main questions in G protein coupled receptors (GPCRs) molecular pharmacology is to understand the structural arrangements of the seven transmembrane (TM) helices that occur to stabilize either the ground state (Rg) or different active states (R*) of the receptors. In order to understand the mechanism that shift the equilibrium of the ensemble to an active R* state models of the inactive and the active state of three serotonin receptors (5-HT4, 5-HT6, and 5-HT7) were built based on the latest information from X-ray crystallography. The resulting models were mainly used to understand the interaction between a ligand and its receptor and the mechanism of action. With the help of pharmacological and chemical data these models and complexes were improved and evaluated. These findings may prove valuable for structural based drug discovery efforts and facilitate the design of more effective and selective pharmaceuticals.