RESUMEN
Our previous scaffold-hopping attempts resulted in dihydropyrazino-benzimidazoles as metabotropic glutamate receptor-2 (mGluR2) positive allosteric modulators (PAMs) with suboptimal drug-like profiles. Here, we report an alternative fragment-based optimization strategy applied on the new dihydropyrazino-benzimidazolone scaffold. Analyzing published high-affinity mGluR2 PAMs, we used a pharmacophore-guided approach to identify suitable growing vectors and optimize the scaffold in these directions. This strategy resulted in a new fragment like lead (34) with improved druglike properties that were translated to sufficient pharmacokinetics and validated proof-of-concept studies in migraine. Gratifyingly, compound 34 showed reasonable activity in the partial infraorbital nerve ligation, a migraine disease model that might open this indication for mGluR2 PAMs.
Asunto(s)
Bencimidazoles/uso terapéutico , Agonistas de Aminoácidos Excitadores/uso terapéutico , Trastornos Migrañosos/tratamiento farmacológico , Pirazinas/uso terapéutico , Receptores de Glutamato Metabotrópico/agonistas , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Agonistas de Aminoácidos Excitadores/síntesis química , Agonistas de Aminoácidos Excitadores/farmacocinética , Masculino , Estructura Molecular , Prueba de Estudio Conceptual , Pirazinas/síntesis química , Pirazinas/farmacocinética , Ratas Wistar , Relación Estructura-ActividadRESUMEN
The aim of the present study was to review neuroprotective therapy from the preclinical point of view as a potential tool for the treatment of stroke, as well as to discuss neuroprotective effects of the apovincaminic acid derivative vinpocetine (Cavinton). Our own in vivo and in vitro experiments were aimed at further characterizing pharmacological effects involved in the vinpocetine-induced neuroprotection. The effect of vinpocetine on infarct volume (obtained by 2,3,5-triphenyltetrazolium-chloride staining) was studied in permanent middle cerebral artery occlusion (MCAO) in rats (3 mg/kg i.p., 30 min postischemia). Vinpocetine treatment significantly decreased infarct volume (by 42%, p < 0.05) compared to control, which was better than the effect of nimodipine (17%) or MK-801 (18%). Neurotoxicity measurements were made in primary cortical cell culture using LDH release as an indicator. Vinpocetine dose-dependently inhibited prolonged (24 h) or transient (15 min) glutamate, and transient N-metil-D-aspartate (NMDA) or veratridine (0.1-1 mM) induced excitotoxicity (IC50 = 2-7 x 10(-6) M). In these tests the neuroprotective potency of vinpocetine was lower than that of MK-801, but it was similar to those of flunarizine or nimodipine. These results together with former literature data indicate that apovincaminic acid derivatives possessing strong neuroprotective potential may play an important role in the therapy of ischemic stroke.