RESUMO
On the basis of the first dipeptide ligand of TSPO, N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide (GD-23), which was obtained by us earlier, we synthesized a new dipeptide, N-phenylpropionyl-L-tryptophanyl-L-leucine amide (GD-102). GD-102 exhibited anxiolytic activity in the open field test in BALB/c mice and in the elevated plus maze test in ICR mice. The minimum effective dose of GD-102 was one order of magnitude lower than that of GD-23. Compound PK11195, a selective antagonist of TSPO, completely blocked the anxiolytic activity of GD-102, which testified to the involvement of TSPO in the realization of the anxiolytic effect of GD-102. The results were confirmed by molecular docking data.
Assuntos
Ansiolíticos/química , Dipeptídeos/química , Simulação de Acoplamento Molecular , Receptores de GABA/química , Ansiolíticos/farmacologia , Dipeptídeos/farmacologia , Humanos , Receptores de GABA/metabolismoRESUMO
The elevated plus maze test showed that GD-23 (N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide), an original dipeptide ligand of TSPO, exerted anxiolytic effect when injected intraperitoneally at a dose of 0.5 mg/kg. This effect was completely blocked by the selective neurosteroid synthesis inhibitors, enzymes trilostane and finasteride. The same inhibitors do not prevent the anxiolytic effects of the benzodiazepine tranquillizer diazepam. The results of the study indicate the selective neurosteroidogenic mechanism of the anxiolytic action of GD-23.
Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Dipeptídeos/farmacologia , Neurotransmissores/biossíntese , Animais , Animais não Endogâmicos , Proteínas de Transporte/metabolismo , Diazepam/farmacologia , Di-Hidrotestosterona/análogos & derivados , Di-Hidrotestosterona/farmacologia , Inibidores Enzimáticos/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Finasterida/farmacologia , Injeções Intraperitoneais , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Receptores de GABA-A/metabolismoRESUMO
On the basis of the structure of Alpidem, a pyrazolopyrimidine ligand of the translocator protein (TSPO), a dipeptide TSPO ligand, N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide (GD-23), was designed and synthesized using our own original peptide design strategy. This compound exhibited anxiolytic activity in BALB/cAnN mice in the "open-field" test and in outbred CD1 mice in the "elevated plus maze" test. The stereoselectivity of the anxiolytic effect of GD-23 is demonstrated. The results of this study suggest that GD-23 is a ligand of the translocator protein, and its structure can become the basis for creating anxiolytics with a fundamentally new mechanism of action.
Assuntos
Ansiolíticos/metabolismo , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Dipeptídeos/metabolismo , Dipeptídeos/farmacologia , Receptores de GABA/metabolismo , Animais , Animais não Endogâmicos , Ansiolíticos/síntese química , Ansiolíticos/química , Fármacos do Sistema Nervoso Central/farmacologia , Dipeptídeos/síntese química , Dipeptídeos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Isoquinolinas/farmacologia , Ligantes , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos BALB C , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologiaRESUMO
A series of 1-arylpyrrolo[1,2-a]pyrazine-3-carboxamides were designed and synthesized as 18kDa translocator protein (TSPO) ligands. Anxiolytic-like activity of compounds was evaluated in the open field test and elevated plus maze test. Compounds 1a and 1b demonstrated high anxiolytic-like effect in the dose range of 0.1-1.0mg/kg comparable with that of diazepam. The involvement of TSPO receptor in the mechanism of anxiolytic-like activity of new compounds was proved by antagonism of the most active compound 1a with TSPO selective inhibitor PK11195. In vitro binding studies demonstrated high TSPO affinities for compounds 1a and 1b.
Assuntos
Amidas/síntese química , Ansiolíticos/síntese química , Ansiedade/tratamento farmacológico , Pirazinas/síntese química , Receptores de GABA/química , Amidas/farmacologia , Animais , Ansiolíticos/farmacologia , Ansiedade/genética , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Sítios de Ligação , Diazepam/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Expressão Gênica , Isoquinolinas/farmacologia , Ligantes , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Atividade Motora/efeitos dos fármacos , Ligação Proteica , Pirazinas/farmacologia , Receptores de GABA/genética , Receptores de GABA/metabolismo , Relação Estrutura-AtividadeRESUMO
The conformational analysis with 1H NMR spectroscopy method in solution and the structure-activity relationship study of a series sterically restricted analogs allowed to detect the possible biologically active conformation of N-(6-phenylhexanoyl)glycyl-tryptophan amide (GB-115), a highly active dipeptide cholecystokinin-4 analog with anxiolytic activity. The structure-activity relationship study of GB-115 and the series of its' glycine- and proline-containing analogs with different C-terminal substitute detected the anxiolytic activity of compounds with beta-turn like conformation and inactivity of compounds with gamma-turn like conformation. So, the GB-115 biologically active conformation is beta-turn. The results of nuclear Overhauser effect study permitted to qualify the betaII-turn conformation as GB-115 biologically active conformation. The following synthesis of sterically restricted GB-115 analogs (2S)-2-{(3R)-3-[(6-phenylhexanoyl)amino]-2-oxopyrrolidin-1-yl}-3-(1H-indol-3-yl)propionic acid ethyl ester, N-(6-phenylhexanoyl)glycyl-N(alpha)(methyl)-tryptophan ethyl ester, (2S)-2-[10,11-dihydro-5H-dibenzo[b,f] azepin-5-carbonyl)-amino]-3-(1H-indol-3-yl)propionic acid methyl ester and (2S)-2-[({3-[(ethoxycarbonyl)amino]-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl}carbonyl)amino]-3-(1H-indol-3-yl)propionic acid methyl ester confirmed the estimated type of GB-115 biologically active conformation.
