Design, synthesis, and anticonvulsant effects evaluation of nonimidazole histamine H₃receptor antagonists/inverse agonists containing triazole moiety

Abstract

Histamine H 3 receptors (H 3 R) antagonists/inverse agonists are becoming a promising therapeutic approach for epilepsy. In this article, novel nonimidazole H 3 R antagonists/inverse agonists have been designed and synthesised via hybriding the H 3 R pharmacophore (aliphatic amine with propyloxy chain) with the 1,2,4-triazole moiety as anticonvulsant drugs. The majority of antagonists/inverse agonists prepared here exerted moderate to robust activities in cAMP-response element (CRE) luciferase screening assay. 1-(3-(4-(3-Phenyl-4 H -1,2,4-triazol-4-yl)phenoxy)propyl)piperidine ( 3l ) and 1-(3-(4-(3-(4-chlorophenyl)-4 H -1,2,4-triazol-4-yl)phenoxy)propyl)piperidine ( 3m ) displayed the highest H 3 R antagonistic activities, with IC 50 values of 7.81 and 5.92 nM, respectively. Meanwhile, the compounds with higher H 3 R antagonistic activities exhibited protection for mice in maximal electroshock seizure (MES)-induced convulsant model. Moreover, the protection of 3m against the MES induced seizures was fully abrogated when mice were co-treated with RAMH, a CNS-penetrant H 3 R agonist, which suggested that the potential therapeutic effect of 3m was through H 3 R. These results indicate that the attempt to find new anticonvulsant among H 3 R antagonists/inverse agonists is practicable.

Synthesis and antiseizure effect evaluation of nonimidazole histamine H3receptor antagonists containing the oxazole moiety

“…The reduction or abolition of the THLE of mice was considered protective against the MES‐induced seizures. [ 23,29,48 ] Test compounds and positive drugs VPA (300 mg/kg) and PIT (10 mg/kg) were intraperitoneally administrated half an hour before the electric stimulation. To investigate the mechanism of action, the most promising compound, 5g , was chosen for a further test.…”

“…Majority of them exhibited moderate‐to‐strong H 3 R inhibitory activities and exhibited antiseizure activity in an animal model of seizure. [ 29 ] JNJ‐6379490 is one of nonimidazole H 3 R antagonists containing an imidazo‐pyrimidine moiety. This compound possesses high potency (p K i = 8.6) as a neutral H 3 R antagonist with good brain penetration (rat: ED 50 = 0.2 mg/kg ip).…”

Molecular Modeling of Histamine Receptors—Recent Advances in Drug Discovery

“…It was identified by using the intramolecular H 3 R biosensor based on bioluminescence resonance energy transfer (BRET) that is sensitive to the conformational dynamics of H 3 R and can be used to screen for the receptor agonists and inverse agonists in a live cell [ 133 ]. Nonimidazole antagonists/inverse agonists of H 3 R with nanomolar activity as anticonvulsant drugs were obtained by Song et al [ 134 ] by linking the H 3 R pharmacophore (aliphatic amine with propyloxy chain) with the 1,2,4-triazole moiety. Docking studies indicated that these ligands were bound to Y 3.33 and E 5.46 , and additionally to R 6.58 , F193 ECL2 and M 6.55 [ 134 ].…”

“…Nonimidazole antagonists/inverse agonists of H 3 R with nanomolar activity as anticonvulsant drugs were obtained by Song et al [ 134 ] by linking the H 3 R pharmacophore (aliphatic amine with propyloxy chain) with the 1,2,4-triazole moiety. Docking studies indicated that these ligands were bound to Y 3.33 and E 5.46 , and additionally to R 6.58 , F193 ECL2 and M 6.55 [ 134 ].…”

An Important Potential Anti-Epileptic/Anticonvulsant Active Group: A Review of 1,2,4-Triazole Groups and Their Action

“…In 2020, novel nonimidazole H 3 R antagonists/inverse agonists, compound 14 in ▶Fig. 4, have been designed and synthesized by Song et al [34]. via hybriding the H 3 R pharmacophore (aliphatic amine with propyloxy chain) with the 1,2,4-triazole moiety as an-ticonvulsant drugs.…”