RESUMEN
The synthesis and pharmacological activity of a new series of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as sigma-1 receptor (σ1R) ligands are reported. A hit from a high-throughput screening program was evolved into a highly potent and selective σ1R agonist (14qR) that contains a free NH group as positive ionizable moiety, not fulfilling the usual pharmacophoric features of the σ1R. The compound shows good physicochemical and ADMET characteristics, displays an agonist profile in the binding immunoglobulin protein/σ1R association assay, induces neuron viability in an in vitro model of ß-amyloid peptide intoxication, and presents positive results against recognition memory impairment induced by hippocampal injection of Aß peptide in rats after oral treatment, altogether making 14qR (WLB-87848) an interesting candidate for neuroprotection.
Asunto(s)
Fármacos Neuroprotectores , Receptores sigma , Receptor Sigma-1 , Animales , Receptores sigma/agonistas , Receptores sigma/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Ratas , Humanos , Masculino , Relación Estructura-Actividad , Péptidos beta-Amiloides/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Pirimidinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/química , Trastornos de la Memoria/tratamiento farmacológico , Supervivencia Celular/efectos de los fármacos , Pirimidinonas/farmacología , Pirimidinonas/síntesis química , Pirimidinonas/química , Ratas Wistar , Hipocampo/efectos de los fármacos , Hipocampo/metabolismoRESUMEN
The synthesis and pharmacological activity of a new series of dual ligands combining activities towards the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) and the µ-opioid receptor (MOR) as novel pain therapeutics are reported. A careful exploration of the pharmacophores related to both targets, which in principle had few common characteristics, led to the design of novel compounds exhibiting both activities. The construction of the dual ligands started from published Cavα2δ-1 ligands, onto which MOR ligand pharmacophoric elements were added. This exercise led to new amino-acidic substances with good affinities on both targets as well as good metabolic and physicochemical profiles and low potential for drug-drug interactions. A representative compound, (2S,4S)-4-(4-chloro-3-(((cis)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid, displayed promising analgesic activities in several inâ vivo pain models as well as a reduced side-effect profile in relation to morphine.
