Synthesis and Biological Evaluation of Novel Triazine Derivatives as Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptors

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 EC 50 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.

Allosteric Activation of α7 Nicotinic Acetylcholine Receptors by Novel 2-Arylamino-thiazole-5-carboxylic Acid Amide Derivatives for the Improvement of Cognitive Deficits in Mice

“…Transmembrane region a is the binding site of PNU120596, as identified by cryo-EM (PDB: 7EKT, ribbon with yellow-green color). Transmembrane region b (PDB: 2BG9, ribbon with platinum color) is the binding site reported by Newcombe (see ref ) and used in our previous article (see ref ); Top: Docking scores of compounds 6p , 7b , the classical type I PAM compound B12, and the typical type II PAM PNU120596 on different transmembrane binding sites. (B) Binding models of the type I PAM 7b and the atypical type I PAM 6p in transmembrane region b.…”

“…Our group has previously identified several series of selective α7 PAMs. − Among them, potent thiazolo­[4,5- d ]­pyrimidin-7­(6 H )-one 4b and a triazine derivative 4c that could enhance α7 current were identified as type I PAMs with the maximum current activation efficacies exceeding 16-fold and 38-fold, respectively, in the presence of acetylcholine (100 μM), a significant improvement made from the initial hit compound 4a (Figure ). The compounds 4b and 4c also exhibited the dose-dependent reversal of prepulse inhibition (PPI) deficit induced by MK-801 in the mouse model of schizophrenia. , …”

“…The compounds 4b and 4c also exhibited the dosedependent reversal of prepulse inhibition (PPI) deficit induced by MK-801 in the mouse model of schizophrenia. 24,25 Our further modifications on the pyrimidin-7(6H)-one ring of compound 4 series resulted in the discovery of a 4-aminothiazole derivative 4d and a 4-amino-2-benzylthiothiazole derivative 5, irrespectively (Figure 2). Compound 4b is a potent type I α7 nAChR PAM (1630%, Figure 2), whereas compound 5 (max effect of 120%, Figure 2 and Table 1) as well as 4d (260%, Figure 2 and Table 1) show no activity.…”

1,4-Disubstituted Piperazin-2-Ones as Selective Late Sodium Current Inhibitors with QT Interval Shortening Properties in Isolated Rabbit Hearts

“…Our research groups have engaged in the identification, screening, and pharmacological studies of ion channel targets and candidate drugs for several years. − Recently, we were inspired to explore a novel selective cardiac Na V 1.5 late I Na inhibitor with high potency from a hybrid structure motif of ranolazine and GS-6615.…”

Divergent Synthesis of α-(1,3,5-Triazinylthio)-ketones and Thiazolo[3,2-a][1,3,5]triazines from 1,3-Dicarbonyl compounds or Chalcones with 1,3,5-Triazine-2-thiols

“…Moreover, 1,3,5-triazine based molecules have been found to exhibit multiple bioactivities such as adenosin receptor antagonists, protein kinases, HIV-1 reverse transcriptase, urate oxidase, estrogen receptor beta, mTOR inhibitors, and so on . In particular, α-(1,3,5-triazinylthio)-ketones have been reported to display various activities, including antitumor activity, antimalarial activity, antibacterial activity, antileishmanial activity, antiviral activity, and for treating neurological disorders. − For this reason, the development of efficient protocols for α-(1,3,5-triazinylthio)-ketones has always been an active area of research in both synthetic and medicinal chemistry. In recent years, several examples of the C–C bond cleavage and C–C or C–heteroatom bond reconstruction of 1,3-dicarbonyl compounds have been reported .…”