RESUMEN
The P4 region of a series of oxamyl dipeptide caspase inhibitors was optimized by the combination of anti-apoptotic activity in the Jurkat/Fas (JFas) cellular assay and membrane permeability in the PAMPA assay. Two highly potent anti-apoptotic agents with moderate membrane permeability, 29 and 36, showed strong in vivo efficacy in a murine model of alpha-Fas-induced liver injury.
Asunto(s)
Inhibidores de Caspasas , Inhibidores de Cisteína Proteinasa/síntesis química , Hepatopatías/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Permeabilidad de la Membrana Celular/efectos de los fármacos , Inhibidores de Cisteína Proteinasa/farmacología , Humanos , Células Jurkat , Ratones , Relación Estructura-Actividad , Receptor fasRESUMEN
We have characterized the pharmacological properties of the novel nociceptin/orphanin FQ peptide receptor (NOP receptor) agonist, 2-(3,5-dimethylpiperazin-1-yl)-1-[1-(1-methylcyclooctyl)piperidin-4-yl]-1H-benzimidazole (PCPB). PCPB bound to the NOP receptor in mouse brain membranes (Ki=0.12 nM) and to recombinant human NOP receptor (Ki=2.1 nM). PCPB showed full agonism for the NOP receptor in isolated mouse vas deferens with a maximal effect and high potency that were similar to the pharmacological profile observed for nociceptin/orphanin FQ (N/OFQ) (pD(2): 6.9+/-0.2; 95+/-2% activity). Orally administered PCPB (30 mg/kg) penetrated well into the brains of the mice. PCPB exhibited an anxiolytic activity in mice subjected to the Vogel conflict test that was comparable to the maximal response induced by diazepam, a representative anxiolytic agent. The anxiolytic effect of PCPB was dose-dependently blocked by the NOP receptor antagonist, J-113397, demonstrating that this effect was mediated by the NOP receptor agonist activity. Behavioral studies in mice also showed that PCPB prolonged the pentobarbital-induced sleeping time but did not cause muscle relaxation at the oral anxiolytic dose of 30 mg/kg. Unlike diazepam, however, these central effects of PCPB were weak. Our results indicate that PCPB is a potent anxiolytic agent with agonistic activities for the NOP receptor.
Asunto(s)
Ansiolíticos/administración & dosificación , Bencimidazoles/administración & dosificación , Encéfalo/efectos de los fármacos , Piperazinas/administración & dosificación , Receptores Opioides/agonistas , Administración Oral , Animales , Ansiolíticos/síntesis química , Ansiolíticos/farmacocinética , Conducta Animal/efectos de los fármacos , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Técnicas In Vitro , Masculino , Ratones , Piperazinas/síntesis química , Piperazinas/farmacocinética , Piperidinas/administración & dosificación , Piperidinas/farmacología , Sueño/efectos de los fármacos , Conducto Deferente/efectos de los fármacos , Conducto Deferente/metabolismo , Receptor de NociceptinaRESUMEN
Novel NR2B antagonists with an amide tether were found by an approach to avoid pharmacophoric similarity to dofetilide. Structure-activity relationship investigation led to N-[cis-4-hydroxy-4-(5-hydroxypyridin-2-yl)cyclohexyl]-3-henylpropanamide as an orally active NR2B-subtype selective N-methyl-D-aspartate (NMDA) receptor antagonist with very weak HERG (human ether-a-go-go related gene) binding (IC(50)> 30 microM). This compound exhibited potent in vivo anti-allodynic activity in the mouse partial sciatic nerve ligation (PSL) model (minimum effective dose=10 mg/kg, po).
