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1.
Molecules ; 25(3)2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31979301

RESUMO

Huntington's disease (HD) is a fatal neurodegenerative disease caused by a CAG expansion mutation in the huntingtin gene. As a result, intranuclear inclusions of mutant huntingtin protein are formed, which damage striatal medium spiny neurons (MSNs). A review of Positron Emission Tomography (PET) studies relating to HD was performed, including clinical and preclinical data. PET is a powerful tool for visualisation of the HD pathology by non-invasive imaging of specific radiopharmaceuticals, which provide a detailed molecular snapshot of complex mechanistic pathways within the brain. Nowadays, radiochemists are equipped with an impressive arsenal of radioligands to accurately recognise particular receptors of interest. These include key biomarkers of HD: adenosine, cannabinoid, dopaminergic and glutamateric receptors, microglial activation, phosphodiesterase 10 A and synaptic vesicle proteins. This review aims to provide a radiochemical picture of the recent developments in the field of HD PET, with significant attention devoted to radiosynthetic routes towards the tracers relevant to this disease.


Assuntos
Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagem , Doença de Huntington/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Encéfalo/patologia , Agonistas de Receptores de Canabinoides/metabolismo , Radioisótopos de Carbono/química , Antagonistas de Dopamina/síntese química , Antagonistas de Dopamina/química , Antagonistas de Dopamina/metabolismo , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/metabolismo , Radioisótopos de Flúor/química , Antagonistas GABAérgicos/síntese química , Antagonistas GABAérgicos/química , Antagonistas GABAérgicos/metabolismo , Humanos , Doença de Huntington/patologia , Microglia/metabolismo , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/metabolismo , Antagonistas de Receptores Purinérgicos P1/síntese química , Antagonistas de Receptores Purinérgicos P1/química , Antagonistas de Receptores Purinérgicos P1/metabolismo , Compostos Radiofarmacêuticos/química
2.
Bioorg Med Chem ; 27(2): 416-424, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30579800

RESUMO

Competitive antagonists (CAs) of ionotropic GABA receptors (GABARs) reportedly exhibit insecticidal activity and have potential for development as novel insecticides for overcoming emerging resistance to traditional GABAR-targeting insecticides. Our previous studies demonstrated that 4,5-disubstituted 3-isoxazolols or 3-isothiazolols are an important class of insect GABAR CAs. In the present study, we synthesized a series of 4-aryl-5-carbamoyl-3-isoxazolols and examined their antagonism of insect GABARs expressed in Xenopus oocytes. Several of these 3-isoxazolols exhibited potent antagonistic activities against housefly and common cutworm GABARs, with IC50 values in the low-micromolar range in both receptors. 4-(3-Amino-4-methylphenyl)-5-carbamoyl-3-isoxazolol (3u) displayed the highest antagonism, with IC50 values of 2.0 and 0.9 µM in housefly and common cutworm GABARs, respectively. Most of the synthesized 3-isoxazolols showed moderate larvicidal activities against common cutworms, with more than 50% mortality at 100 µg/g. These results indicate that 4-monocyclic aryl-5-carbamoyl-3-isoxazolol is a promising scaffold for insect GABAR CA discovery and provide important information for the design and development of GABAR-targeting insecticides with a novel mode of action.


Assuntos
Carbamatos/farmacologia , Antagonistas GABAérgicos/farmacologia , Proteínas de Insetos/antagonistas & inibidores , Inseticidas/farmacologia , Isoxazóis/farmacologia , Animais , Carbamatos/síntese química , Carbamatos/química , Domínio Catalítico , Antagonistas GABAérgicos/síntese química , Antagonistas GABAérgicos/química , Moscas Domésticas , Proteínas de Insetos/química , Inseticidas/síntese química , Inseticidas/química , Isoxazóis/síntese química , Isoxazóis/química , Simulação de Acoplamento Molecular , Receptores de GABA/química , Spodoptera , Xenopus/genética
3.
J Med Chem ; 61(6): 2422-2446, 2018 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-29481759

RESUMO

Recent reports indicate that α6ß2/3γ2 GABAAR selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally α6ß2/3γ2 GABAAR selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABAAR α6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive α6ß2/3γ2 GABAARs and were functionally silent at diazepam sensitive α1ß2/3γ2 GABAARs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABAAR α6ß2/3γ2 subtypes.


Assuntos
Antagonistas GABAérgicos/síntese química , Antagonistas GABAérgicos/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Animais , Ansiolíticos/síntese química , Ansiolíticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Disponibilidade Biológica , Deutério , Desenho de Fármacos , Feminino , Antagonistas GABAérgicos/farmacocinética , Células HEK293 , Humanos , Hipnóticos e Sedativos/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos , Atividade Motora/efeitos dos fármacos , Força Muscular/efeitos dos fármacos , Ratos , Ratos Wistar , Especificidade por Substrato
4.
Bioorg Med Chem ; 22(17): 4637-45, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-25112550

RESUMO

γ-Aminobutyric acid (GABA) receptors are important targets of parasiticides/insecticides. Several 4-substituted analogs of the partial GABAA receptor agonist 5-(4-piperidyl)-3-isothiazolol (Thio-4-PIOL) were synthesized and examined for their antagonism of insect GABA receptors expressed in Drosophila S2 cells or Xenopus oocytes. Thio-4-PIOL showed weak antagonism of three insect GABA receptors. The antagonistic activity of Thio-4-PIOL was enhanced by introducing bicyclic aromatic substituents into the 4-position of the isothiazole ring. The 2-naphthyl and the 3-biphenylyl analogs displayed antagonist potencies with half maximal inhibitory concentrations in the low micromolar range. The 2-naphthyl analog induced a parallel rightward shift of the GABA concentration-response curve, suggesting competitive antagonism by these analogs. Both compounds exhibited weak insecticidal activities against houseflies. Thus, the orthosteric site of insect GABA receptors might be a potential target site of insecticides.


Assuntos
Antagonistas GABAérgicos/farmacologia , Piperidinas/farmacologia , Receptores de GABA/metabolismo , Tiazóis/farmacologia , Animais , Ligação Competitiva/efeitos dos fármacos , Relação Dose-Resposta a Droga , Antagonistas GABAérgicos/síntese química , Antagonistas GABAérgicos/química , Moscas Domésticas , Inseticidas/síntese química , Inseticidas/química , Inseticidas/farmacologia , Modelos Moleculares , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
5.
Org Biomol Chem ; 9(12): 4685-94, 2011 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-21541379

RESUMO

Expansion of the D-ring of 19-norsteroids with incorporation of the steroid C-18 methyl group into a newly formed six-membered ring provides easy access to the chrysene ring system. By taking advantage of the symmetry of the chrysene ring system and avoiding meso chrysene intermediates, four optically pure 2,8-difunctionalized (C-2 hydroxyl group and C-8 oxo group) hexadecahydrochrysene diastereomers, and their corresponding optically pure enantiomers were prepared from 19-nortestosterone. The eight chrysene stereoisomers are of interest as starting materials for preparing chrysene analogues of physiologically important neurosteroids.


Assuntos
Química Farmacêutica/métodos , Crisenos/síntese química , Agonistas GABAérgicos/síntese química , Antagonistas GABAérgicos/síntese química , Nandrolona/química , Neurotransmissores/síntese química , Androgênios/química , Cromatografia em Camada Fina , Crisenos/análise , Agonistas GABAérgicos/análise , Antagonistas GABAérgicos/análise , Humanos , Espectroscopia de Ressonância Magnética , Neurotransmissores/análise , Pregnanos/química , Receptores de GABA/metabolismo , Estereoisomerismo
6.
Pest Manag Sci ; 66(9): 1002-10, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20730993

RESUMO

BACKGROUND: Bicyclophosphorothionates (2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane-1-sulfides) are blockers (or non-competitive antagonists) of gamma-aminobutyric acid (GABA) receptor channels. Twenty-two bicyclophosphorothionates with different 3- and 4-substituents were synthesised, and [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB) binding assays were performed to evaluate their affinities for housefly and rat GABA receptors. RESULTS: Introduction of an isopropyl group at the 3-position enhanced the affinity of bicyclophosphorothionates for housefly GABA receptors and reduced the affinity towards rat GABA receptors. The 4-isopentyl-3-isopropylbicyclophosphorothionate showed the highest affinity for housefly GABA receptors (IC(50) = 103 nM) among the analogues tested, while the 4-cyclohexylbicyclophosphorothionate showed the highest affinity for rat GABA receptors (IC(50) = 125 nM). Among the bicyclophosphorothionates synthesised to date, the former analogue exhibited the highest selectivity for housefly GABA receptors, with an IC(50)(rat)/IC(50)(fly) ratio of approximately 97. Three-dimensional GABA receptor models successfully explained the structure-activity relationships of the bicyclophosphorothionates. CONCLUSION: The results indicate that minor structural modifications of blockers can change their selectivity for insect versus mammalian GABA receptors. The substituent at the 3-position of the bicyclophosphorothionates dictates selectivity for housefly versus rat GABA receptors. This information should prove useful for the design of safer insecticides and parasiticides.


Assuntos
Antagonistas GABAérgicos/química , Antagonistas GABAérgicos/farmacologia , Moscas Domésticas/efeitos dos fármacos , Moscas Domésticas/metabolismo , Fosfitos/química , Fosfitos/farmacologia , Receptores de GABA/metabolismo , Sequência de Aminoácidos , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Antagonistas GABAérgicos/síntese química , Antagonistas GABAérgicos/metabolismo , Moscas Domésticas/fisiologia , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Fosfitos/síntese química , Fosfitos/metabolismo , Conformação Proteica , Ratos , Receptores de GABA/química , Relação Estrutura-Atividade , Especificidade por Substrato
7.
J Med Chem ; 53(8): 3417-21, 2010 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-20355712

RESUMO

A series of substituted 1-hydroxypyrazole analogues of the GABA(A) receptor partial agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL) have been synthesized and pharmacologically characterized. Several of the analogues displayed K(i) in the low nanomolar range at the native GABA(A) receptors and potent antagonism of the alpha(1)beta(2)gamma(2) receptor. It appears that several regions situated in proximity to the core of the orthosteric binding site of the GABA(A) receptor are able to accommodate large hydrophobic substituents.


Assuntos
Antagonistas GABAérgicos/síntese química , Piperidinas/síntese química , Pirazóis/síntese química , Receptores de GABA-A/metabolismo , Animais , Linhagem Celular , Antagonistas GABAérgicos/química , Antagonistas GABAérgicos/farmacologia , Inibidores da Captação de GABA , Humanos , Interações Hidrofóbicas e Hidrofílicas , Técnicas In Vitro , Ligantes , Potenciais da Membrana/efeitos dos fármacos , Modelos Moleculares , Piperidinas/química , Piperidinas/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Ratos , Relação Estrutura-Atividade , Membranas Sinápticas/efeitos dos fármacos , Membranas Sinápticas/fisiologia
8.
Neurochem Res ; 34(10): 1704-11, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19387831

RESUMO

GABA(C) receptors play a role in myopia, memory-related disorders and circadian rhythms signifying a need to develop potent and selective agents for this class of receptors. Guanidino analogs related to glycine, beta-alanine and taurine were evaluated at human rho(1)GABA(C) receptors expressed in Xenopus oocytes using 2-electrode voltage clamp methods. Of the 12 analogs tested, 8 analogs were active as antagonists and the remaining were inactive. (S)-2-guanidinopropionic acid (IC(50) = 2.2 microM) and guanidinoacetic acid (IC(50) = 5.4 microM; K (B) = 7.75 microM [pK (B) = 5.11 +/- 0.06]) were the most potent being competitive antagonists at this receptor. In contrast, the beta-alanine and GABA guanidino analogs showed reduced activity, indicating the distance between the carboxyl carbon and terminal nitrogen of the guanidino group is critical for activity. Substituting the C2-position of guanidinoacetic acid with various alkyl groups reduced activity indicating that steric effects may impact on activity. The results of this study contribute to the structure-activity-relationship profile required in developing novel therapeutic agents.


Assuntos
Antagonistas GABAérgicos/farmacologia , Glicina/análogos & derivados , Guanidinas/farmacologia , Propionatos/farmacologia , Receptores de GABA/metabolismo , Animais , Relação Dose-Resposta a Droga , Feminino , Antagonistas GABAérgicos/síntese química , Antagonistas GABAérgicos/metabolismo , Glicina/síntese química , Glicina/metabolismo , Glicina/fisiologia , Guanidinas/síntese química , Guanidinas/metabolismo , Humanos , Oócitos/química , Oócitos/metabolismo , Propionatos/síntese química , Propionatos/metabolismo , Receptores de GABA/biossíntese , Receptores de GABA/genética , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Taurina/análogos & derivados , Taurina/síntese química , Taurina/metabolismo , Xenopus laevis , beta-Alanina/metabolismo
9.
Org Lett ; 11(2): 309-12, 2009 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19072699

RESUMO

A new flexible strategy for the synthesis of diversely functionalized pyridazines from 4-chloro-1,2-diaza-1,3-butadienes and active methylene compounds is reported. The high chemoselectivity of this approach offers access to structural precursors of GABA-A antagonist analogues.


Assuntos
Antagonistas GABAérgicos/síntese química , Piridazinas/síntese química , Butadienos/química , Antagonistas GABAérgicos/química , Piridazinas/química , Especificidade por Substrato
10.
Bioorg Med Chem ; 17(1): 94-110, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19062297

RESUMO

The gamma-aminobutyric acid (GABA) receptor bears important sites of action for insecticides. Alantrypinone is an insecticidal alkaloid that acts as a selective antagonist for housefly (vs rat) GABA receptors, and is considered to be a lead compound for the development of a safer insecticide. In an attempt to obtain compounds with greater activity, a series of racemic alantrypinone derivatives were systematically synthesized using hetero Diels-Alder reactions, and a total of 34 compounds were examined for their ability to inhibit the specific binding of [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate, a high-affinity non-competitive antagonist, to housefly-head membranes. The assay results showed that (1) there is no significant difference between the potencies of natural (+)-alantrypinone and its synthetic racemate; (2) the amide NHs at the 2- and 18-positions are important for high activity; (3) there is a considerable drop in potency for compounds without an aromatic ring at the 16-position; and (4) a large substituent at the 3-position is detrimental to high activity.


Assuntos
Alcaloides/síntese química , Antagonistas GABAérgicos/síntese química , Indóis/síntese química , Inseticidas/síntese química , Quinazolinas/síntese química , Alcaloides/farmacologia , Animais , Ligação Competitiva , Moscas Domésticas , Indóis/farmacologia , Inseticidas/farmacologia , Quinazolinas/farmacologia , Ratos , Receptores de GABA/efeitos dos fármacos , Relação Estrutura-Atividade
11.
J Med Chem ; 51(13): 3825-40, 2008 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-18528996

RESUMO

Gamma-aminobutyric acid (GABA) analogues based on 4-amino-cyclopent-1-enyl phosphinic acid ( 34- 42) and 3-aminocyclobutane phosphinic acids ( 51, 52, 56, 57) were investigated in order to obtain selective homomeric rho 1 GABA C receptor antagonists. The effect of the stereochemistry and phosphinic acid substituent of these compounds on potency and selectivity within the GABA receptor subtypes was investigated. Compounds of high potency at GABA C rho 1 receptors ( 36, K B = 0.78 microM) and selectivity greater than 100 times ( 41, K B = 4.97 microM) were obtained. The data obtained was analyzed along with the known set of GABA C rho 1 receptor-ligands, leading to the development of a pharmacophore model for this receptor, which can be used for in silico screening.


Assuntos
Antagonistas GABAérgicos/síntese química , Antagonistas GABAérgicos/farmacologia , Animais , Feminino , Antagonistas GABAérgicos/química , Ligantes , Modelos Moleculares , Estrutura Molecular , Oócitos/efeitos dos fármacos , Relação Estrutura-Atividade , Xenopus laevis
12.
Carbohydr Res ; 343(10-11): 1840-8, 2008 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-18378220

RESUMO

We describe the synthesis of sugar-fused beta-disubstituted gamma-butyrolactones, gamma-butyrolactams and a lipophilic beta-disubstituted GABA analogue as potential GABA receptor ligands, where the pharmacophore is engineered into the carbohydrate scaffold in the form of a C-fructoside. The products were characterized for receptor binding studies of GABA(A) receptors.


Assuntos
4-Butirolactona/análogos & derivados , 4-Butirolactona/química , Frutose/análogos & derivados , Frutose/química , Agonistas GABAérgicos/química , Lactamas/química , Animais , Ligação Competitiva , Encéfalo/metabolismo , Agonistas GABAérgicos/síntese química , Antagonistas GABAérgicos/síntese química , Antagonistas GABAérgicos/química , Lactamas/síntese química , Ligantes , Muscimol/química , Ratos
13.
Bioorg Med Chem Lett ; 17(13): 3769-73, 2007 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-17517506

RESUMO

A series of new (R)-1-(2-diarylmethylthio/sulfinyl)ethyl-piperidine-3-carboxylic acid hydrochlorides 5a-d/6a-d and (R)-1-(3-diarylmethylthio)propyl-piperidine-3-carboxylic acid hydrochlorides 5'a-d were synthesized and evaluated as gamma-aminobutyric acid uptake inhibitors through cultured cell lines expressing mouse GAT1. Biological screening results demonstrated that the compounds 6a-d with diarylmethylsulfinyl ethyl side chain show more potent GAT1 inhibitory activities than 5a-d/5'a-d with diarylmethylthio ethyl/propyl moieties. Some of them, such as 6a, exhibited excellent inhibitions of [(3)H]-GABA uptake in cultured cells, which is 496-fold higher than (R)-nipecotic acid and 11.5 times less than tiagabine. The synthesis and structure-activity relationships are discussed.


Assuntos
Ácidos Carboxílicos/síntese química , Química Farmacêutica/métodos , Antagonistas GABAérgicos/síntese química , Proteínas da Membrana Plasmática de Transporte de GABA/fisiologia , Piperidinas/síntese química , Ácido gama-Aminobutírico/farmacocinética , Animais , Anticonvulsivantes/química , Ácidos Carboxílicos/química , Desenho de Fármacos , Antagonistas GABAérgicos/química , Proteínas da Membrana Plasmática de Transporte de GABA/química , Imidazóis/química , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Ácidos Nipecóticos/química , Ácidos Nipecóticos/farmacologia , Piperidinas/química , Relação Estrutura-Atividade , Temperatura , Tiagabina
14.
J Agric Food Chem ; 54(4): 1361-72, 2006 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-16478261

RESUMO

To study the interaction of phenylheterocycles with gamma-aminobutyric acid (GABA) receptors, 4- or 5-alkyl(or phenyl)-1-phenyl-1H-1,2,3-triazoles were synthesized and examined for their ability to inhibit the specific binding of [3H]-4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB), a noncompetitive antagonist, to the housefly and rat GABA receptors, as well as to the beta3 subunit homo-oligomer of the human GABA receptor investigated as a model receptor. 4-Substituted 1-phenyl-1H-1,2,3-triazoles were found to be more potent competitive inhibitors than the 5-substituted regioisomers in the case of all receptors. The 4-tert-butyl or 4-n-propyl analogue of 1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-1,2,3-triazole exhibited the highest level of inhibition of [3H]EBOB binding to all receptors. Most of the synthesized analogues were more active in terms of the inhibition of EBOB binding to the housefly and human beta3 GABA receptors than to the rat receptor. The 4-cyclohexyl analogue showed the highest (185-fold) housefly versus rat receptor selectivity. A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis demonstrated that both the 4-trifluoromethyl-2,6-dichloro substitution on the phenyl ring and a small, bulky, hydrophobic substituent at the 4-position of the triazole ring played significant roles in conferring high potency in cases involving the housefly and human beta3 receptors. The human beta3 receptor resembled the housefly receptor in terms of their recognition of phenyltriazoles, whereas 3D-QSAR analysis revealed a slight difference between the two receptors in terms of their mechanisms of recognition of the para-substituent on the phenyl moiety. Some of the triazoles synthesized here exhibited insecticidal activity, which was correlated with their ability to inhibit [3H]EBOB binding to the housefly receptor. Thus, 1-phenyl-1H-1,2,3-triazoles with the appropriate substituents exert insecticidal activity by selectively acting at the site for noncompetitive antagonism of insect GABA receptors.


Assuntos
Antagonistas GABAérgicos/síntese química , Inseticidas , Receptores de GABA/efeitos dos fármacos , Triazóis/síntese química , Triazóis/farmacologia , Sequência de Aminoácidos , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Cristalografia por Raios X , Antagonistas GABAérgicos/química , Moscas Domésticas , Humanos , Dados de Sequência Molecular , Relação Quantitativa Estrutura-Atividade , Ratos , Receptores de GABA/química , Receptores de GABA/metabolismo , Relação Estrutura-Atividade , Triazóis/química
15.
J Org Chem ; 70(20): 7911-8, 2005 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-16277310

RESUMO

[Chemical reaction: See text] A convenient preparation of functionalized chiral tetrahydropyridine-3-carboxylates from nitriles in 68-90% enantiomeric excess (ee) via allylboration, followed by a conjugate addition-elimination and ring-closing metathesis, has been developed. Thus, the treatment of the acetate derived from vinylalumination of formaldehyde by use of [alpha-(ethoxycarbonyl)vinyl]diisobutylaluminum with chiral beta-substituted and beta-unsubstituted homoallylic amines, prepared in >98% diastereomeric excess (de) and 68-90% ee via allylboration of the corresponding N-aluminoimines, furnished functionalized aminodienes, which underwent ring-closing metathesis to provide chiral C5-C6 disubstituted tetrahydropyridine-3-carboxylates. This methodology has been applied for the synthesis of a chiral C6-substituted tetrahydropyridine with known GABA-inhibiting properties at low concentrations.


Assuntos
Aminas/síntese química , Antagonistas GABAérgicos/síntese química , Piridinas/síntese química , Alumínio , Aminas/química , Catálise , Antagonistas GABAérgicos/química , Espectroscopia de Ressonância Magnética , Piridinas/química , Compostos de Vinila
17.
Eur J Med Chem ; 40(3): 231-47, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15725493

RESUMO

Several synthetic approaches to N-alkylated derivatives of 4-hydroxypyrrolidine-2-carboxylic acid and 4-hydroxypyrrolidine-2-acetic acid are described. The final compounds have been evaluated as potential inhibitors of the GABA transport proteins GAT-1 and GAT-3. The biological assays used were based on bovine material or porcine brain. As compared to the corresponding 4-unsubstituted compounds, the 4-hydroxypyrrolidine-2-carboxylic acid and 4-hydroxypyrrolidine-2-acetic acid derivatives showed a significant decrease in the inhibitory potency at both GAT-1 and GAT-3 with only four compounds having reasonable affinity to GAT-1 (IC(50): 5.1, 6.6 and 9.4 microM) or GAT-3 (IC(50): 19.9 microM), respectively. The biological data of the 4-hydroxypyrrolidine-2-acetic acid derivatives indicates that (2S)-configuration at the C-2 position for potent inhibition of GAT-1 and (4R)-configuration at the C-4 position for potent inhibition of GAT-3 may be crucial.


Assuntos
Antagonistas GABAérgicos/síntese química , Antagonistas GABAérgicos/farmacologia , Moduladores de Transporte de Membrana , Proteínas de Membrana Transportadoras/antagonistas & inibidores , Prolina/análogos & derivados , Prolina/química , Animais , Transporte Biológico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Bovinos , Proteínas da Membrana Plasmática de Transporte de GABA , Estrutura Molecular , Relação Estrutura-Atividade , Suínos , Ácido gama-Aminobutírico/metabolismo
18.
Bioorg Med Chem ; 13(3): 895-908, 2005 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-15653355

RESUMO

A series of lipophilic diaromatic derivatives of the glia-selective GABA uptake inhibitor (R)-4-amino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol [(R)-exo-THPO, 4] were synthesized via reductive amination of 3-ethoxy-4,5,6,7-tetrahydrobenzo[d]isoxazol-4-one (9) or via N-alkylation of O-alkylatedracemic 4. The effects of the target compounds on GABA uptake mechanisms in vitro were measured using a rat brain synaptosomal preparation or primary cultures of mouse cortical neurons and glia cells (astrocytes), as well as HEK cells transfected with cloned mouse GABA transporter subtypes (GAT1-4). The activity against isoniazid-induced convulsions in mice after subcutaneous administration of the compounds was determined. All of the compounds were potent inhibitors of synaptosomal uptake the most potent compound being (RS)-4-[N-(1,1-diphenylbut-1-en-4-yl)amino]-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol (17a, IC50 = 0.14 microM). The majority of the compounds showed a weak preference for glial, as compared to neuronal, GABA uptake. The highest degree of selectivity was 10-fold corresponding to the glia selectivity of (R)-N-methyl-exo-THPO (5). All derivatives showed a preference for the GAT1 transporter, as compared with GAT2-4, with the exception of (RS)-4-[N-[1,1-bis(3-methyl-2-thienyl)but-1-en-4-yl]-N-methylamino]-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol (28d), which quite surprisingly turned out to be more potent than GABA at both GAT1 and GAT2 subtypes. The GAT1 activity was shown to reside in (R)-28d whereas (R)-28d and (S)-28d contributed equally to GAT2 activity. This makes (S)-28d a GAT2 selective compound, and (R)-28d equally effective in inhibition of GAT1 and GAT2 mediated GABA transport. All compounds tested were effective as anticonvulsant reflecting that these compounds have blood-brain barrier permeating ability.


Assuntos
Antagonistas GABAérgicos/síntese química , Antagonistas GABAérgicos/farmacologia , Isoxazóis/síntese química , Isoxazóis/farmacologia , Animais , Espectroscopia de Ressonância Magnética , Camundongos , Ratos
19.
J Med Chem ; 47(23): 5620-9, 2004 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-15509161

RESUMO

Three of twelve secoergoline derivatives (Z ethyl 4-[(ethoxycarbonylmethyl)methylamino]-2-methyl-3-phenylpent-2-enoate, 8; ethyl 1,6-dimethyl-3-oxo-5-phenyl-1,2,3,6-tetrahydropyridine-2-carboxylate, 9; Z methyl 4-[(methoxycarbonylmethyl)methylamino)-2-methyl-3-phenylpent-2-enoate, 11), containing bioisosteric sequences of GABA and Glu, inhibited both GABA and Glu transport through cerebrocortical membranes specifically. Compounds 8, 9, and 11 appeared to be equipotent inhibitors of GABA and Glu transport with IC50 values between 270 and 1100 microM, whereas derivatives 1-7, 10, and 12 were without effects. In the presence of GABA and Glu transport-specific nontransportable inhibitors, inhibition of GABA and Glu transport by 8, 9, and 11 proceeded in two phases. The two phases of inhibition were characterized by IC50 values between 4 and 180 nM and 360-1020 microM and different selectivity sequences. These findings may indicate the existence of some mechanism possibly mediated by a previously unrecognized GABA-Glu transporter. Derivatives with the cis, but not the trans configuration of bulky ester groups (8 vs 7 and 11 vs 12) showed significant inhibitory effect (IC50 values of 270 microM vs >>1000 microM and 1100 microM vs >>1000 microM on GABA transport, respectively). The cis-trans selectivity can be explained by docking these secoergolines in a three-dimensional model of the second and third transmembrane helices of GABA transporter type 1.


Assuntos
Aminoácidos/síntese química , Encéfalo/efeitos dos fármacos , Ergolinas/síntese química , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas GABAérgicos/síntese química , Ácido Glutâmico/metabolismo , Ácido gama-Aminobutírico/metabolismo , Aminoácidos/química , Aminoácidos/farmacologia , Animais , Transporte Biológico/efeitos dos fármacos , Encéfalo/metabolismo , Ergolinas/química , Ergolinas/farmacologia , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas GABAérgicos/química , Antagonistas GABAérgicos/farmacologia , Técnicas In Vitro , Masculino , Modelos Moleculares , Ensaio Radioligante , Ratos , Ratos Wistar , Estereoisomerismo , Relação Estrutura-Atividade
20.
Mol Pharmacol ; 65(5): 1191-7, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15102947

RESUMO

Although neurosteroids have rapid effects on GABA(A) receptors, study of steroid actions at GABA receptors has been hampered by a lack of pharmacological antagonists. In this study, we report the synthesis and characterization of a steroid analog, (3alpha,5alpha)-17-phenylandrost-16-en-3-ol (17PA), that selectively antagonized neurosteroid potentiation of GABA responses. We examined 17PA using the alpha1beta2gamma2 subunit combination expressed in Xenopus laevis oocytes. 17PA had little or no effect on baseline GABA responses but antagonized both the response augmentation and the direct gating of GABA receptors by 5alpha-reduced potentiating steroids. The effect was selective for 5alpha-reduced potentiating steroids; 5beta-reduced potentiators were only weakly affected. Likewise, 17PA did not affect barbiturate and benzodiazepine potentiation. 17PA acted primarily by shifting the concentration response for steroid potentiation to the right, suggesting the possibility of a competitive component to the antagonism. 17PA also antagonized 5alpha-reduced steroid potentiation and gating in hippocampal neurons and inhibited anesthetic actions in X. laevis tadpoles. Analogous to benzodiazepine site antagonists, the development of neurosteroid antagonists may help clarify the role of GABA-potentiating neurosteroids in health and disease.


Assuntos
Androstenóis/farmacologia , Antagonistas GABAérgicos/farmacologia , Antagonistas de Receptores de GABA-A , Neurônios/efeitos dos fármacos , Androstenóis/síntese química , Androstenóis/química , Animais , Sinergismo Farmacológico , Antagonistas GABAérgicos/síntese química , Antagonistas GABAérgicos/química , Hipocampo/citologia , Neurônios/metabolismo , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Esteroides/química , Esteroides/farmacologia , Xenopus laevis
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