RESUMEN
Accumulating evidence suggests that modulating the sigma 2 receptor (Sig2R) can provide beneficial effects for neurodegenerative diseases. Herein, we report the identification of a novel class of Sig2R ligands and their cellular and in vivo activity in experimental models of Alzheimer's disease (AD). We report that SAS-0132 and DKR-1051, selective ligands of Sig2R, modulate intracellular Ca2+ levels in human SK-N-SH neuroblastoma cells. The Sig2R ligands SAS-0132 and JVW-1009 are neuroprotective in a C. elegans model of amyloid precursor protein-mediated neurodegeneration. Since this neuroprotective effect is replicated by genetic knockdown and knockout of vem-1, the ortholog of progesterone receptor membrane component-1 (PGRMC1), these results suggest that Sig2R ligands modulate a PGRMC1-related pathway. Last, we demonstrate that SAS-0132 improves cognitive performance both in the Thy-1 hAPPLond/Swe+ transgenic mouse model of AD and in healthy wild-type mice. These results demonstrate that Sig2R is a promising therapeutic target for neurocognitive disorders including AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Trastornos del Conocimiento/metabolismo , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Fármacos Neuroprotectores/metabolismo , Receptores sigma/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/prevención & control , Animales , Línea Celular Tumoral , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/prevención & control , Relación Dosis-Respuesta a Droga , Humanos , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/metabolismo , Mediadores de Inflamación/antagonistas & inhibidores , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/uso terapéutico , Unión Proteica/fisiología , Receptores sigma/antagonistas & inhibidores , Receptores sigma/genéticaRESUMEN
A novel structural class with high affinity and subtype selectivity for the sigma 2 receptor has been discovered. Preliminary structure-affinity relationship data are presented showing that 8-substituted 1,3,4,5-tetrahydro-1,5-methanobenzazepine (norbenzomorphan) derivatives elicit modest to high selectivity for the sigma 2 over the sigma 1 receptor subtype. Indeed, piperazine analogue 8-(4-(3-ethoxy-3-oxopropyl)piperazin-1-yl)-1,3,4,5-tetrahydro-1,5-methanobenzazepine-2-carboxylate (SAS-1121) is 574-fold selective for the sigma 2 over the sigma 1 receptor, thereby establishing it as one of the more subtype-selective sigma 2 binding ligands reported to date. Emerging evidence has implicated the sigma 2 receptor in multiple health disorders, so the drug-like characteristics of many of the selective sigma 2 receptor ligands disclosed herein, coupled with their structural similarity to frameworks found in known drugs, suggest that norbenzomorphan analogues may be promising candidates for further development into drug leads.