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1.
J Med Chem ; 57(15): 6809-21, 2014 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-25025595

RESUMO

Inhibition of mGAT1, the most abundant GABA transporter in the brain, enhances GABA signaling and alleviates symptoms of CNS disorders such as epilepsy assumed to be associated with low GABA levels. We have now developed a potent and subtype selective photoswitchable inhibitor of this transporter, which for the first time extends the photoswitch concept for the light-induced control of ligand affinity to active membrane transporters. The new inhibitor exhibited reduced activity upon irradiation with light, as demonstrated in GABA uptake assays and electrophysiological experiments with brain slices, and might be used as a tool compound for deepening the understanding of mGAT1 function in brain.


Assuntos
Compostos Azo/química , Encéfalo/efeitos dos fármacos , Encéfalo/efeitos da radiação , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Inibidores da Captação de GABA/química , Ácidos Nipecóticos/química , Animais , Compostos Azo/síntese química , Compostos Azo/farmacologia , Encéfalo/metabolismo , Inibidores da Captação de GABA/síntese química , Inibidores da Captação de GABA/farmacologia , Células HEK293 , Humanos , Luz , Masculino , Camundongos Endogâmicos C57BL , Ácidos Nipecóticos/síntese química , Ácidos Nipecóticos/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
2.
Bioorg Med Chem ; 21(11): 3363-78, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23598250

RESUMO

γ-Amino butyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system (CNS). A malfunction of the GABAergic neurotransmission is connected to several neuronal disorders like epilepsy, Alzheimer's disease, neuropathic pain, and depression. One possibility to enhance GABA levels in the synaptic cleft is to inhibit mGAT1, one of the four known plasma membrane bound GABA transporters, which is considered the most important GABA transporter subtype, being in charge of the removal of GABA from the synaptic cleft after a neuronal impulse. Lipophilic derivatives of nipecotic acid like Tiagabine (Gabitril®), an approved drug used in add-on therapy of epilepsy, are known to inhibit uptake of mGAT1 with high subtype selectivity and affinity. We synthesized new N-substituted nipecotic acid derivatives with a vinyl ether spacer and an unsymmetrical bis-aromatic residue, which carries fluorine substituents at various positions of the aromatic ring-system. The new compounds were characterized with respect to their potency and subtype selectivity as mGAT1 inhibitors.


Assuntos
Anticonvulsivantes/síntese química , Membrana Celular/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de GABA/química , Inibidores da Captação de GABA/síntese química , Fármacos Neuroprotetores/síntese química , Ácidos Nipecóticos/síntese química , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Transporte Biológico , Membrana Celular/metabolismo , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Inibidores da Captação de GABA/química , Inibidores da Captação de GABA/farmacologia , Células HEK293 , Humanos , Camundongos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Ácidos Nipecóticos/química , Ácidos Nipecóticos/farmacologia , Relação Estrutura-Atividade , Compostos de Vinila/química , Ácido gama-Aminobutírico/metabolismo
3.
Angew Chem Int Ed Engl ; 48(12): 2228-30, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19199304

RESUMO

An animalic note: The first total synthesis of the all-cis nupharamine 2, an alkaloid from beaver castoreum, is based on the stereoselective domino Mannich-Michael reaction of N-galactosylfurylaldimine to give 1 (Piv = pivaloyl), subsequent conjugate cuprate addition, and stereoselective protonation of the enolate. These reactions are all controlled by the carbohydrate. Protonation of the enolate after cleavage of the auxiliary leads to epimer 3.


Assuntos
Alcaloides/síntese química , Furanos/síntese química , Piperidinas/síntese química , Alcaloides/química , Animais , Furanos/química , Indolizidinas/química , Piperidinas/química , Roedores , Glândulas Odoríferas , Estereoisomerismo , Terpenos/química
4.
Bioconjug Chem ; 20(2): 317-21, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19132825

RESUMO

Radiosyntheses of 18F-radiopharmaceuticals for positron emission tomography (PET) normally require an extraordinarily high effort of technical equipment and specially trained personnel. We recently reported a novel method for the introduction of fluorine-18 into peptides for PET-imaging based on silicon-18F-chemistry (SiFA technique). We herewith introduce the first SiFA-based Kit-like radio-fluorination of a protein (rat serum albumin,RSA) and demonstrate its usefulness for in vivo imaging with microPET in normal rats as well as in a rat heterotropic transplanted heart model. As a labeling agent, we prepared 4-(di-tert-butyl[18F]fluorosilyl)benzenethiol (Si[18F]FASH)by simple isotopic exchange in 40-60% radiochemical yield (RCY) and coupled it directly to a Sulfo-SMCC derivatized RSA in an overall RCY of 12% within 20-30 min. The technically simple labeling procedure does not require any elaborated purification procedures and is a straightforward example of a successful application of Si-18F chemistry for in vivo imaging with PET.


Assuntos
Radioisótopos de Flúor/química , Compostos de Organossilício/síntese química , Compostos de Organossilício/metabolismo , Kit de Reagentes para Diagnóstico , Albumina Sérica/química , Coloração e Rotulagem/métodos , Animais , Estudos de Viabilidade , Imagem do Acúmulo Cardíaco de Comporta , Coração/diagnóstico por imagem , Compostos de Organossilício/química , Tomografia por Emissão de Pósitrons , Ratos , Albumina Sérica/metabolismo , Albumina Sérica/farmacocinética , Distribuição Tecidual
5.
Chemistry ; 15(9): 2140-7, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19156812

RESUMO

Broad spectrum: Novel para-functionalized aryl-di-tert-butylfluorosilanes, p-(tBu(2)FSi)C(6)H(4)X (X=functional group), have been made available and broaden the spectrum of silicon-based (18)F acceptors (SiFAs) for potential PET applications. For example, the [(18)F]maleimido derivative 1 has been employed for the synthesis of [(18)F]1- labeled rat serum albumin (RSA), the applicability of which for PET has been verified by in vivo experiments.The syntheses of the functionalized triorganofluorosilanes tBu(2)(p-XC(6)H(4))SiF (3 a, X=SH; 4 a, X=NCS; 4 b, X=NCO; 5, X=NC(4)H(2)O(2); 7, X=COOH; 8 a, X=COONC(4)H(4)O(2); 8 b, X=COOC(6)F(5)) are reported. These compounds display potential as silicon-based fluoride acceptors (SiFAs). The molecular structures of compounds 5, 7, and 8 a have been determined by single-crystal X-ray diffraction studies. With the exception of compounds 8 a and 8 b, all of the compounds could be (18)F-labeled by isotopic exchange in good to high radiochemical yields (RCY) with good to excellent specific activities. As proof of applicability, the maleimido-functionalized SiFA derivative 5, which is specific for thiol groups, has been used for the labeling of rat serum albumin (RSA) that had been derivatized with 2-iminothiolane. The incorporation of [(18)F]5 into the derivatized RSA reached a maximum yield after 30 min at ambient temperature. After purification, the [(18)F]RSA was evaluated in a healthy rat by means of muPET and displayed an expedient in vivo stability over 180 min.


Assuntos
Radioisótopos de Flúor , Hidrocarbonetos Fluorados/síntese química , Compostos Radiofarmacêuticos/síntese química , Silanos/síntese química , Animais , Cristalografia por Raios X , Hidrocarbonetos Fluorados/sangue , Hidrocarbonetos Fluorados/química , Masculino , Conformação Molecular , Estrutura Molecular , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/química , Ratos , Silanos/química , Estereoisomerismo
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