RESUMEN
Pyrrolylquinoxalinediones carrying aminoalkyl residues were evaluated for affinity to the recombinant, homomeric kainate receptors GluR5, GluR6 and GluR7. Most derivatives preferred binding to GluR5. In particular, the piperazine 6e represents a highly potent and selective antagonist to GluR5.
Asunto(s)
Piperazinas/química , Piperazinas/metabolismo , Quinoxalinas/química , Quinoxalinas/metabolismo , Receptores de Ácido Kaínico/metabolismo , Animales , Sitios de Unión , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/síntesis química , Antagonistas de Aminoácidos Excitadores/química , Antagonistas de Aminoácidos Excitadores/metabolismo , Antagonistas de Aminoácidos Excitadores/farmacología , Ligandos , Ratones , Estructura Molecular , N-Metilaspartato/farmacología , Piperazinas/síntesis química , Piperazinas/farmacología , Quinoxalinas/síntesis química , Quinoxalinas/farmacología , Receptores de Ácido Kaínico/antagonistas & inhibidores , Receptores de Ácido Kaínico/química , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Relación Estructura-Actividad , Especificidad por Sustrato , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacologíaRESUMEN
Novel calpain inhibitors derived from phenyl alanine aldehydes or ketoamides carrying a benzoyl residue were prepared and evaluated for their biological potency. A brief structure-activity relationship elucidated the importance of ortho-substitutents in the benzoyl moiety. The most potent derivative, the ketoamide 19c, exhibited a K(i) of 6nM and represents a novel class of reversible, highly potent and non-peptidic calpain inhibitors.
Asunto(s)
Calpaína/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/síntesis química , Cetoácidos/síntesis química , Fenilalanina , Amidas/síntesis química , Amidas/farmacología , Plaquetas/enzimología , Calpaína/sangre , Inhibidores de Cisteína Proteinasa/farmacología , Diseño de Fármacos , Humanos , Cetoácidos/farmacología , Modelos Moleculares , Conformación Molecular , Relación Estructura-ActividadRESUMEN
Calpain inhibitors which are derived from piperidine carboxamides in the P2 region were prepared and evaluated for mu-calpain inhibition. In particular, the keto amides 11f and 11j have Ki of 30 and 9 nM and display a more than 100-fold selectivity over the closely related cysteine protease cathepsin B. Furthermore, these compounds inhibit NMDA induced convulsions in mice indicating that calpain inhibition in brain results in some anticonvulsive properties.
Asunto(s)
Calpaína/antagonistas & inhibidores , Oligopéptidos/síntesis química , Oligopéptidos/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Catepsina B/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacología , Dipéptidos/química , Dipéptidos/farmacología , Evaluación Preclínica de Medicamentos , Ratones , Estructura Molecular , Oligopéptidos/química , Piperidinas/química , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Antagonists at the ionotropic non-NMDA [AMPA (amino-methyl proprionic acid)/kainate] type of glutamate receptors have been suggested to possess several advantages compared to NMDA (N-methyl-D-aspartate) receptor antagonists, particularly in terms of risk/benefit ratio, but the non-NMDA receptor antagonists available so far have not fulfilled this promise. From a large series of pyrrolyl-quinoxalinedione derivatives, we selected six new competitive non-NMDA receptor antagonists. The basis of selection was high potency and selectivity for AMPA and/or kainate receptors, high in vivo potency after systemic administration, and an acceptable ratio between neuroprotective or anticonvulsant effects and adverse effects. Pharmacological characteristics of these novel compounds are described in this study with special emphasis on their effects in the kindling model of temporal lobe epilepsy, the most common type of epilepsy in humans. In most experiments, NBQX and the major antiepileptic drug valproate were used for comparison with the novel compounds. The novel non-NMDA receptor antagonists markedly differed in their AMPA and kainate receptor affinities from NBQX. Thus, while NBQX essentially did not bind to kainate receptors at relevant concentrations, several of the novel compounds exhibited affinity to rat brain kainate receptors or recombinant kainate receptor subtypes in addition to AMPA receptors. One compound, LU 97175, bound to native high affinity kainate receptors and rat GluR5-GluR7 subunits, i.e. low affinity kainate binding sites, with much higher affinities than to AMPA receptors. All compounds potently blocked AMPA-induced cell death in vitro and, except LU 97175, AMPA-induced convulsions in vivo. In the kindling model, compounds with a high affinity for GluR7 (LU 97175) or compounds (LU 115455, LU 136541) which potently bind to AMPA receptors and low affinity kainate receptor subunits were potent anticonvulsants in the kindling model, whereas the AMPA receptor-selective LU 112313 was the least selective compound in this model, indicating that non-NMDA antagonists acting at both AMPA and kainate receptors are more effective in this model than AMPA receptor-selective drugs. Three of the novel compounds, i.e. LU 97175, LU 115455 and LU 136541, exerted potent anticonvulsant effects without inducing motor impairment in the rotarod test. This combination of actions is thought to be a prerequisite for selective anticonvulsant drug action.