ABSTRACT
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.
Subject(s)
Nicotinic Agonists/therapeutic use , Schizophrenia/drug therapy , Triazines/therapeutic use , alpha7 Nicotinic Acetylcholine Receptor/agonists , Animals , Dizocilpine Maleate , Female , Humans , Male , Mice, Inbred C57BL , Molecular Docking Simulation , Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/metabolism , Nicotinic Agonists/pharmacokinetics , Schizophrenia/chemically induced , Sensory Gating/drug effects , Triazines/chemical synthesis , Triazines/metabolism , Triazines/pharmacokinetics , Xenopus laevis , alpha7 Nicotinic Acetylcholine Receptor/metabolismABSTRACT
Structural modifications of nicotinamide, a form of vitamin B3, gave rise to a series of compounds (8aa-8ce) that exhibit activities as type I positive allosteric modulators (PAMs) of human α7 nAChR expressed in Xenopus oocytes in two-electrode voltage clamp assay. The compound 8ai was a potent and efficacious PAM with an EC50â¯=â¯3.34⯱â¯1.13⯵M and the maximum activation effect of α7 current over 1474⯱â¯246% in the presence of acetylcholine (100⯵M). It is highly specific to α7 nAChR over other subtypes of nAChR and 5-HT3A receptors. The structure-activity relationship analysis identified a key skeleton of nicotinamide nucleus critical for biological activity. Taken together, the 8ai as a type I PAM of α7 nAChR may be beneficial for improvement of cognitive deficit.
Subject(s)
Nicotinic Agonists/therapeutic use , alpha7 Nicotinic Acetylcholine Receptor/drug effects , Allosteric Regulation , Humans , Nicotinic Agonists/pharmacology , Structure-Activity RelationshipABSTRACT
A series of novel thiazolo[4,5- d]pyrimidin-7(6 H)-ones (3aa-3eq) were designed, synthesized, and evaluated as the type I positive allosteric modulators of human α7 nAChR expressed in Xenopus ooctyes by a two-electrode voltage clamp. The structure-activity relationship analysis identified the compound 3ea as a potent and efficacious PAM with the maximum activation effect of the α7 current of over 1633% in the presence of acetylcholine (100 µM) and an EC50 = 1.26 µM. It is highly specific to α7 nAChR over other subtypes of nAChR, 5-HT3A, NMDA, and GABAA receptors. Compound 3ea showed an elimination half-life of 10.8 ± 1.5 h for 3 mg/kg, i.v., and 7.4 ± 1.1 h for 60 mg/kg, i.g. in rat. It also exhibited sufficient blood-brain barrier penetration with no significant effect on hERG channel. Most importantly, compound 3ea dose-dependently (0.1-1 mg/kg, i.p.) reversed the prepulse inhibition deficit induced by MK-801 in the mouse schizophrenia model.
