No description available.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

No description available.

No description available.

Ziel dieser Arbeit war die Synthese von (RS)-5-Amino-3-aryl(methyl)-pentansäure Hydrochloride, 3-Aminomethyl-5-chlor-benzolsäure Hydrochlorid und(RS)-4-Amino-3-(4´-ethynyl(jod)-phenyl)-butansäure Hydrochloride und die Testung der pharmakologischen Aktivität dieser Verbindungen. Die synthetisierten Verbindungen wurden als GABAB-Rezeptor Agonisten, in einem auf Ca2+-Messungen basierenden Funktional-Assay (in vitro tsA Zellen mit GABAB1b/GABAB2/Gαq-z5 transfektiert), getestet und daraus ein Struktur-Aktivitäts Modell abgeleitet. Im allgemein Teil dieser Arbeit wird ein Überblick, über die Neurotransmitter- Rezeptoren (Liganden gesteuerte Ionen-Kanal-Rezeptoren und G Protein-gekoppelte Rezeptoren) des zentralen Nervensystems und deren Agonisten und Antagonisten, gegeben. Eine ausführliche Diskussion zur Synthesestrategie der Verbindungen der Zwischenstufen und der Ausgangsmaterialien wird in den Schemata 2-6 beschrieben. Die synthetisierten Verbindungen wurden als GABAB Agonisten geprüft. Zusätzlich wurden diese im 3D Homologie Modell mit FlexiDock Programm gedockt. Daraus wurde ein Modell zur Voraussage der Aktivität von Analogen und Homologen des Baclofens abgeleitet. Letztendlich wurde ein Pharmakophor-Modell für GABAB Agonisten mit DISCO (DIStance COmparisons) Programm erstellt. / Synthesis of (RS)-5-amino-3-aryl (methyl)-pentanoic acid hydrochlorides, 3 aminomethyl-5-chloro-benzoic acid hydrochloride and (RS)-4-amino-3-(4`-ethynyl(iodo)-phenyl)-butanoic acid hydrochlorides have been accomplished. The aim of their synthesis was to evaluate their GABABR agonist activity and to derive a model which will correlate their structure with the observed pEC50. The GABABR agonist activity of the prepared compounds has been determined in functional assay based on calcium measurement in vitro using tsA cells transfected with GABAB1b/GABAB2/Gαq-z5. Reviews on the neurotransmitter receptors (ligand-gated ion channel receptors and G protein-coupled receptors), their agonists and antagonists have been given in the general part of this work. A detailed discussion on the strategy followed for the synthesis of the designed compounds as well as the starting materials and intermediates has been described and illustrated in Schemes 2-6. The synthesized compounds were evaluated for their GABABR agonist activity. Furthermore, these compounds were docked in the available 3D homology model of GABABR using the program FlexiDock implemented in SYBYL software. Subsequently, we derived a predictive model which correlates the experimentally determined pEC50 with the calculated binding energy of certain baclofen analogues and homologues. In addition, we used the program DISCO (DIStance COmparisons) implemented in SYBYL software to find the pharmacophore features of GABAB agonists.

Thesis advisor: Stephen C. Heinrichs / This study investigated the effects of baclofen, a GABAB agonist, on modulating drug seeking and drug reward in a novel model of reinstatement. To investigate drug seeking, rats were trained to nosepoke for cocaine infusions, given a drug holiday, and under a baclofen pretreatment (0, 0.2, 1, or 5 mg/kg i.p.), were exposed to an odor conditioned discriminative stimulus (DS+) that reinstated cocaine self-administration. To investigate drug reward, an odor reactivity test was used. Rats were tested for changes in odor preference after the acquisition, drug holiday, and reinstatement phases of self-administration behavior were each completed. Pretreatment with the low dose of baclofen (0.2) attenuated cocaine seeking primed by a conditioned DS+. Medium doses (1.0) caused no change in drug seeking. High doses (5.0) caused a reduction in drug seeking, but this was due to motor impairment. No doses of baclofen had any affect on the rewarding properties of cocaine or cocaine-associated stimuli. It can be concluded that GABAB receptors have no role in modulating the rewarding properties of drug rewards or drug-associated stimuli, but instead play a role in modulating drug seeking. In rats that were exposed to a drug in the past, low levels of GABAB receptor activation reduce drug-seeking, while medium to high levels could have reduced dopamine levels to the point that increased drug seeking or motor impairment was seen. / Thesis (BA) — Boston College, 2004. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Psychology. / Discipline: College Honors Program.

We have explored a formal [3+2] strategy that is synthetically useful for constructing polysubstituted pyroglutamates with three contiguous chiral centers in one step. Base-induced coupling/cyclization reactions of a-sulfonylacetamide with various ethyl (Z)-2-bromo-2-propenoates have been carried out. This reaction with high diastereoselectivity has been applied to the synthesis of Rolipram, Chlorpheg, Baclofen, Pseudoheliotridane and Kainic acid.

Orientador: Eliana Marisa ganem / Resumo: A espasticidade leva a perda na qualidade de vida, capacidade funcional do indivíduo e a alterações psicossociais. O baclofeno é fármaco relaxante muscular de ação central, utilizado no tratamento da espasticidade e é substância análoga ao ácido gama amino-butírico (GABA). Sua administração por via subaracnoidea permite que doses pequenas sejam utilizadas, minimizando efeitos adversos. A pesquisa consistiu em determinar os efeitos da administração de baclofeno em dose única, no espaço subaracnoideo de coelhos, sobre a medula espinal e as meninges. Foram utilizados coelhos, divididos em três grupos: G1, G2 e G3, com injeção no espaço subaracnoideo de soro fisiológico, baclofeno 100 μg e 200 μg respectivamente. Posteriormente foram realizadas as análises histológicas das meninges e medula dos coelhos. Os resultados da presente pesquisa mostram que o baclofeno, independe da dose administrada, causou lesão de tecido nervoso e de meninges em 20% (n=8) dos coelhos estudados. As alterações histológicas foram predominantemente observadas na região posterior das meninges. Podemos concluir que neste modelo experimental em coelhos o baclofeno desencadeou reação inflamatória no tecido nervoso e nas meninges. / Abstract: Spasticity leads to a reduced quality of life, functional capacity limitations, and changes in the psychosocial well-being of an individual. Baclofen is a centrally acting muscle relaxant that is used in the treatment of spasticity and is an analog of gammaamino-butyric acid. Its administration via the subarachnoid route allows the use of small doses, thus minimizing adverse effects. The aim of the study was to determine the effects of administration of a single dose of baclofen into the subarachnoid space of rabbits, on the spinal cord and meninges. Methods: The rabbits were divided into three groups. The first group (G1) was injected with saline solution. The second and third groups (G2 and G3) received 100 and 200 μg of baclofen in the subarachnoid space, respectively. Histological analysis of the meninges and spinal cord in rabbits was subsequently performed. The present findings showed that baclofen, regardless of the administered dose, caused damage to the nerve tissue and meninges in 20% (n = 8) of the tested rabbits. The histological changes were predominantly observed in the posterior portion of the meninges. We conclude that, in this rabbit experimental model, baclofen caused an inflammatory reaction in the nervous tissue and meninges. / Doutor

Submitted by ROBERTO BEZERRA Vital (roberto_vital@hotmail.com) on 2018-04-04T15:41:01Z No. of bitstreams: 1 Projeto v20.pdf: 3872313 bytes, checksum: d68e1cb15df36178f16f81f28f1b8bc8 (MD5) / Rejected by ROSANGELA APARECIDA LOBO null (rosangelalobo@btu.unesp.br), reason: Solicitamos que realize uma nova submissão seguindo as orientações abaixo: Necessário fazer as seguintes correções no arquivo submetido: problema 1: o arquivo submetido não contém capa, item obrigatório de acordo com as normas do seu programa Assim que tiver efetuado as correções submeta o arquivo em PDF novamente. Agradecemos a compreensão. on 2018-04-06T13:09:41Z (GMT) / Submitted by ROBERTO BEZERRA Vital (roberto_vital@hotmail.com) on 2018-04-10T22:23:33Z No. of bitstreams: 1 Roberto Vital (pós-defesa) com capa.pdf: 967175 bytes, checksum: c356f4d0b76b71e6f5e73e048a0fb341 (MD5) / Approved for entry into archive by ROSANGELA APARECIDA LOBO null (rosangelalobo@btu.unesp.br) on 2018-04-11T12:04:37Z (GMT) No. of bitstreams: 1 vital_rb_dr_bot.pdf: 967175 bytes, checksum: c356f4d0b76b71e6f5e73e048a0fb341 (MD5) / Made available in DSpace on 2018-04-11T12:04:37Z (GMT). No. of bitstreams: 1 vital_rb_dr_bot.pdf: 967175 bytes, checksum: c356f4d0b76b71e6f5e73e048a0fb341 (MD5) Previous issue date: 2018-03-01 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A espasticidade leva a perda na qualidade de vida, capacidade funcional do indivíduo e a alterações psicossociais. O baclofeno é fármaco relaxante muscular de ação central, utilizado no tratamento da espasticidade e é substância análoga ao ácido gama amino-butírico (GABA). Sua administração por via subaracnoidea permite que doses pequenas sejam utilizadas, minimizando efeitos adversos. A pesquisa consistiu em determinar os efeitos da administração de baclofeno em dose única, no espaço subaracnoideo de coelhos, sobre a medula espinal e as meninges. Foram utilizados coelhos, divididos em três grupos: G1, G2 e G3, com injeção no espaço subaracnoideo de soro fisiológico, baclofeno 100 μg e 200 μg respectivamente. Posteriormente foram realizadas as análises histológicas das meninges e medula dos coelhos. Os resultados da presente pesquisa mostram que o baclofeno, independe da dose administrada, causou lesão de tecido nervoso e de meninges em 20% (n=8) dos coelhos estudados. As alterações histológicas foram predominantemente observadas na região posterior das meninges. Podemos concluir que neste modelo experimental em coelhos o baclofeno desencadeou reação inflamatória no tecido nervoso e nas meninges. / Spasticity leads to a reduced quality of life, functional capacity limitations, and changes in the psychosocial well-being of an individual. Baclofen is a centrally acting muscle relaxant that is used in the treatment of spasticity and is an analog of gammaamino-butyric acid. Its administration via the subarachnoid route allows the use of small doses, thus minimizing adverse effects. The aim of the study was to determine the effects of administration of a single dose of baclofen into the subarachnoid space of rabbits, on the spinal cord and meninges. Methods: The rabbits were divided into three groups. The first group (G1) was injected with saline solution. The second and third groups (G2 and G3) received 100 and 200 μg of baclofen in the subarachnoid space, respectively. Histological analysis of the meninges and spinal cord in rabbits was subsequently performed. The present findings showed that baclofen, regardless of the administered dose, caused damage to the nerve tissue and meninges in 20% (n = 8) of the tested rabbits. The histological changes were predominantly observed in the posterior portion of the meninges. We conclude that, in this rabbit experimental model, baclofen caused an inflammatory reaction in the nervous tissue and meninges. / Fapesp 2011/ 22262-1

Whole-cell patch recordings were made from immature (six- to 12-day- old) rat rostral ventrolateral medulla neurons in brainstem slices. GABA or the specific GABA(B) receptor agonist (-)baclofen (10-50 μM) by superfusion or by pressure ejection induced an outward current or a hyperpolarization, which persisted in a tetrodotoxin (0.3 μM)-containing Krebs' solution in nearly every cell tested. The GABA(B) receptor antagonists 2-hydroxy saclofen (50-200 μM) and CGP 35348 (50-200 μM) dose-dependently suppressed baclofen- currents. Baclofen-currents were suppressed by barium (1 mM) but not by tetraethylammonium (20 mM), low Ca2+ (0.24 mM) solution or in a solution containing the Ca2+ chelator BAPTA-AM (10 μM). The outward current had an estimated reversal potential of -98, -77 and -52 mV in 3.1, 7 and 15 mM [K+](o). Pre-incubation of slices with pertussis toxin (500 μg/ml for 5-7 h) or intracellular dialysis with GDP-β-S (500 μM) markedly reduced baclofen-currents. Baclofen in low concentrations (1-3 μM) that caused slight or no change of holding currents and of inward or outward currents induced by exogenously applied glutamate or glycine/GABA, decreased excitatory and inhibitory postsynaptic currents by an average of 86.5 ± 4.3% and 78.4 ± 2.7%. The GABA(B) antagonist CGP 35348 (100 μM) increased the excitatory postsynaptic currents by an average of 64%, without causing a significant change in holding currents in 10/18 cells tested. Our results indicate the presence of post- and presynaptic GABA(B) receptors in the rostral ventrolateral medulla neurons. Activation of postsynaptic GABA(B) receptors induces an outward K+ current which is barium-sensitive, Ca2+- independent and may be coupled to a pertussis-sensitive G-protein. Activation of presynaptic GABA(B) receptors attenuates excitatory or inhibitory synaptic transmission. More importantly, the observation that CGP 35348 enhanced excitatory synaptic currents implies a removal of tonic activation of presynaptic GABA(B) receptors by endogenously released GABA (disinhibition), supporting the hypothesis that these receptors may have a physiological role in regulating the input and output ratio in a subset of rostral ventrolateral medulla neurons in vivo.