RESUMO
A series of 1,3-dihydro-2,1,3-benzothiadiazol-2,2-diones (I) and 3,4-dihydro-1H-2,1,3-benzothidiazin-2,2-diones (II) were prepared. While the five-member ring series (I) did not show good affinity for opioid receptors, the six-member ring series (II) exhibited extremely high affinity and selectivity for the NOP receptor and showed full agonist activity, as determined by stimulation of GTPgamma[35S] binding.
Assuntos
Receptores Opioides mu/agonistas , Tiazinas/síntese química , Tiazóis/síntese química , Animais , Humanos , Técnicas In Vitro , Ligantes , Ensaio Radioligante , Ratos , Receptores Opioides mu/metabolismo , Relação Estrutura-Atividade , Tiazinas/química , Tiazinas/farmacologia , Tiazóis/química , Tiazóis/farmacologiaRESUMO
In the search for more efficacious drugs to treat neuropathic pain states, a series of phenoxyphenyl pyridines was designed based on 4-(4-flurophenoxy)benzaldehyde semicarbazone. Through variation of the substituents on the pyridine ring, several potent state-dependent sodium channel inhibitors were identified. From these compounds, 23 dose dependently reversed tactile allodynia in the Chung model of neuropathic pain. Administered orally at 10 mg/kg the level of reversal was ca. 50%, comparable to the effect of carbamazepine administered orally at 100 mg/kg.
Assuntos
Analgésicos/síntese química , Piridinas/síntese química , Bloqueadores dos Canais de Sódio/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Animais Recém-Nascidos , Encéfalo/metabolismo , Linhagem Celular , Humanos , Técnicas In Vitro , Masculino , Canal de Sódio Disparado por Voltagem NAV1.2 , Proteínas do Tecido Nervoso/antagonistas & inibidores , Dor/tratamento farmacológico , Dor/fisiopatologia , Medição da Dor , Doenças do Sistema Nervoso Periférico/fisiopatologia , Piridinas/química , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio , Relação Estrutura-AtividadeRESUMO
Structure-activity studies on benzamide 1 obtained from library screening led to the discovery of a novel series of potent and selective glycine transporter type-2 inhibitors.
Assuntos
Sistemas de Transporte de Aminoácidos Neutros/antagonistas & inibidores , Benzamidas/química , Glicina/metabolismo , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Animais , Benzamidas/metabolismo , Benzamidas/farmacologia , Células CHO , Cricetinae , Glicina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Glicina , HumanosRESUMO
A series of 4-(2-pyridyl)piperazine-1-carboxamide analogues based on the lead compound 1 was synthesized and evaluated for VR1 antagonist activity in capsaicin-induced (CAP) and pH (5.5)-induced (pH) FLIPR assays in a rat VR1-expressing HEK293 cell line. Potent VR1 antagonists were identified through SAR studies. From these studies, 18 was found to be very potent in the in vitro assay [IC(50)=4.8 nM (pH) and 35 nM (CAP)] and orally available in rat (F%=15.1).
