RESUMO
Amino acid derivatives of 1,2,5-thiadiazol-3-yl-piperazine related to (+)-WAY-100135 and WAY-100635 are potent 5-HT1A receptor agonists and antagonists, which have selective affinity for 5-HT1A receptors versus alpha1 and dopamine (D2, D3, and D4) receptors.
Assuntos
Piperazinas/química , Piridinas/química , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Tiadiazóis/química , Tiadiazóis/farmacologia , Aminoácidos/química , Animais , Células CHO , Cricetinae , Feminino , Humanos , Concentração Inibidora 50 , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Receptores 5-HT1 de Serotonina , Antagonistas da Serotonina/química , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Tiadiazóis/metabolismoRESUMO
A series of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)ones and 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines was shown to exhibit 5-HT2C agonist binding and functional activity. Compound 21R inhibited food intake over 2 h in fasted, male Sprague Dawley rats with ED50 values of 2 mg/kg (i.p.) and 10 mg/kg (p.o.).
Assuntos
Depressores do Apetite/síntese química , Pirazinas/síntese química , Quinoxalinas/síntese química , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/síntese química , Animais , Depressores do Apetite/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Pirazinas/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2C de Serotonina , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
Muscarinic M1 preferring agonists may improve cognitive deficits associated with Alzheimer's disease. Side effect assessment of the M1 preferring agonist WAY-132983 showed significant salivation (10 mg/kg i.p. or p.o.) and produced dose-dependent hypothermia after i. p. or p.o. administration. WAY-132983 significantly reduced scopolamine (0.3 mg/kg i.p.)-induced hyperswimming in mice. Cognitive assessment in rats used pretrained animals in a forced choice, 1-h delayed nonmatch-to-sample radial arm maze task. WAY-132983 (0.3 mg/kg i.p) significantly reduced scopolamine (0.3 mg/kg s.c.)-induced errors. Oral WAY-132983 attenuated scopolamine-induced errors; that is, errors produced after combining scopolamine and WAY-132983 (to 3 mg/kg p.o.) were not significantly increased compared with those of vehicle-treated control animals, whereas errors after scopolamine were significantly higher than those of control animals. With the use of miniosmotic pumps, 0.03 mg/kg/day (s.c.) WAY-132983 significantly reduced AF64A (3 nmol/3 microliter/lateral ventricle)-induced errors. Verification of AF64A cholinotoxicity showed significantly lower choline acetyltransferase activity in the hippocampi of AF64A-treated animals, with no significant changes in the striatal or frontal cortex. Cognitive assessment in primates involved the use of pretrained aged animals in a visual delayed match-to-sample procedure. Oral WAY-132983 significantly increased the number of correct responses during short and long delay interval testing. These effects were also apparent 24 h after administration. WAY-132983 exhibited cognitive benefit at doses lower than those producing undesirable effects; therefore, WAY-132983 is a potential candidate for improving the cognitive status of patients with Alzheimer's disease.
Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Cognição/efeitos dos fármacos , Agonistas Muscarínicos/farmacologia , Pirazinas/farmacologia , Animais , Aziridinas/farmacologia , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Colina/análogos & derivados , Colina/farmacologia , Colina O-Acetiltransferase/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Hipotermia/induzido quimicamente , Macaca mulatta , Masculino , Camundongos , Agonistas Muscarínicos/administração & dosagem , Agonistas Muscarínicos/toxicidade , Bloqueadores Neuromusculares/farmacologia , Pirazinas/administração & dosagem , Pirazinas/toxicidade , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Salivação/efeitos dos fármacos , Escopolamina/farmacologia , Tiadiazóis/farmacologia , Fatores de Tempo , Córtex Visual/efeitos dos fármacos , Córtex Visual/metabolismoRESUMO
Rational drug design utilizing a receptor homology model of the human muscarinic M1 receptor led to the discovery of the highly potent (Ki = 2 nM), efficacious, and in vivo functionally-selective M1 agonist, WAY-132983.
