RESUMEN
A series of N-alkyl-N-arylmethylpiperidin-4-amines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake.
Asunto(s)
Norepinefrina/antagonistas & inhibidores , Piperidinas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Piperidinas/química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Relación Estructura-ActividadRESUMEN
The syntheses of a range of ring and alpha-substituted 4-phosphonophenylglycines are described. A brief discussion of the antagonist activities of compounds 4-10 on group I, II and III metabotropic glutamate (mGlu) receptors expressed in the neonatal rat spinal cord is included.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/síntesis química , Glicina/análogos & derivados , Glicina/síntesis química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Antagonistas de Aminoácidos Excitadores/química , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Glicina/química , Glicina/farmacología , Masculino , Ratas , Ratas Wistar , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-ActividadRESUMEN
The cyclobutylglycine (+/-)-2-amino-2-(3-cis and trans-carboxycyclobutyl-3-(9-thioxanthyl)propionic acid) (LY393053) has been identified as a functionally potent metabotropic glutamate receptor antagonist. It is most potent on the two group I metabotropic glutamate receptors, 1alpha and 5alpha, with IC50 values of 1.0+/-0.4 microM and 1.6+/-1.4 microM, respectively. In this study, LY393053 has also been evaluated electrophysiologically on native group I metabotropic glutamate receptors in an in vitro spinal cord preparation as well as behaviourally, in a mouse model of visceral pain. LY393053 dose-dependently antagonised group I agonist, (RS)-3, 5-dihydroxyphenylglycine, or a broad-spectrum agonist (1S,3R)-amino-1,3-cyclopentanedicarboxylic acid-induced depolarisation of spinal motoneurons. The apparent Kd values were estimated to be 0.3 microM against (RS)-3, 5-dihydroxyphenylglycine-induced depolarisation and 0.5 microM against (1S,3R)-amino-1,3-cyclopentanedicarboxylic acid-induced depolarisation, respectively. On the other hand, the dorsal root-ventral root potential elicited at 8 x threshold was depressed by LY393053 with IC50 values of 9.0+/-0.7 microM and 12.7+/-1.7 microM on monosynaptic and polysynaptic responses, respectively. When investigated using the mouse acetic acid writhing test, LY393053 showed significant analgesic effects at doses of 1-10 mg/kg intraperitoneally. An ED50 value of 6.0 mg/kg was obtained in this test. By revealing a potent effect of LY393053 in antagonising the native group I metabotropic receptor-mediated responses in the spinal cord in rodents, and an antinociceptive efficacy in a mouse visceral pain model, these results, therefore, provide additional evidence in support of the analgesic potential of metabotropic glutamate receptor antagonists.
Asunto(s)
Animales Recién Nacidos/fisiología , Dolor/fisiopatología , Propionatos/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Médula Espinal/fisiopatología , Ácido Acético , Animales , Cicloleucina/análogos & derivados , Cicloleucina/farmacología , Electrofisiología , Antagonistas de Aminoácidos Excitadores/farmacología , Glicina/análogos & derivados , Glicina/farmacología , Técnicas In Vitro , Ratones , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/fisiología , Fármacos Neuroprotectores/farmacología , Nociceptores/efectos de los fármacos , Dolor/inducido químicamente , Ratas , Ratas Sprague-Dawley , Resorcinoles/farmacología , Raíces Nerviosas Espinales/efectos de los fármacos , Raíces Nerviosas Espinales/fisiología , EstereoisomerismoRESUMEN
The role of group I metabotropic glutamate (mGlu) receptors in neurodegeneration is controversial because of the contradictory effects of mGlu1/5 agonists in in vitro models of neuronal cell death. In this study, novel and selective antagonists of mGlu1 and mGlu5: LY367385 and LY367366 were found to show consistent neuroprotective effects against N-methyl-D-aspartate (NMDA)-induced excitotoxicity in vitro and in vivo. Furthermore, intraventricular administration of LY367385 reduced hippocampal cell death in gerbils subjected to transient global ischemia. Previous studies have also shown that activation of group II mGlu receptors may contribute to neuroprotective mechanisms in vitro and in vivo. Three potent group II mGlu agonists--LY354740, LY379268 and LY389795--were found to attenuate both NMDA excitotoxicity and staurosporine-induced neuronal cell death. LY354740 and LY379268 were protective against transient global ischemia in gerbils when dosed intraperitoneally. These results support the view that antagonists of mGlu1 and mGlu5 and agonists of group II mGlu receptors may be useful agents in the therapeutic treatment of neurodegenerative disease.