RESUMEN
Enhancing α7 nAChR function serves as a therapeutic strategy for cognitive disorders. Here, we report the synthesis and evaluation of 2-arylamino-thiazole-5-carboxylic acid amide derivatives 6-9 that as positive allosteric modulators (PAMs) activate human α7 nAChR current expressed in Xenopus ooctyes. Among the 4-amino derivatives, a representative atypical type I PAM 6p exhibits potent activation of α7 current with an EC50 of 1.3 µM and the maximum activation effect on the current over 48-fold in the presence of acetylcholine (100 µM). The structure-activity relationship (SAR) analysis reveals that the 4-amino group is crucial for the allosteric activation of α7 currents by compound 6p as the substitution of 4-methyl group results in its conversion to compound 7b (EC50 = 2.1 µM; max effect: 58-fold) characterized as a typical type I PAM. Furthermore, both 6p and 7b are able to rescue auditory gating deficits in mouse schizophrenia-like model of acoustic startle prepulse inhibition.
Asunto(s)
Tiazoles , Receptor Nicotínico de Acetilcolina alfa 7 , Animales , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Regulación Alostérica/efectos de los fármacos , Relación Estructura-Actividad , Humanos , Tiazoles/farmacología , Tiazoles/química , Tiazoles/síntesis química , Tiazoles/uso terapéutico , Ratones , Xenopus laevis , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Ácidos Carboxílicos/síntesis química , Amidas/química , Amidas/farmacología , Amidas/síntesis química , Masculino , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismoRESUMEN
Enhancing neuronal α7 nicotinic acetylcholine receptor (α7 nAChR) function can alleviate cognitive deficits. Here, we report the design, synthesis, and evaluation of N-(4-(trifluoromethoxy)phenyl)-1,3,5-triazin-2-amine derivatives 8-10 as a series of novel α7 nAChR positive allosteric modulators (PAMs). The representative compound 10e functions as a type I PAM with an EC50 of 3.0 µM and approximately 38-fold enhancement of α7 current in the presence of agonist acetylcholine (100 µM). It specifically enhances α7 current with high selectivity. Compound 10e shows good pharmacokinetic property in mice. Intraperitoneal injection of 10e (3 mg/kg) exhibits sufficient blood-brain barrier penetration in mice. Furthermore, 10e can also rescue the auditory gating deficit in mice with schizophrenia-like behavior. Molecular docking of 10e with homopentameric α7 nAChR reveals a new mode of action. These results support the potential of 10e for treatment for schizophrenia and Alzheimer's disease.