Modification of the Structure of 4, 6‐Disubstituted 2‐(4‐Alkyl‐1‐piperazinyl)pyridines: Synthesis and Their 5‐HT_2A Receptor Activity

Abstract

Structure-activity relationship studies of a series of novel 4, 6-disubstituted 2-(1-piperazinyl)pyridines were conducted to revise our model of serotonin 5-HT(2A) receptor antagonist. Target compounds were synthesized using the benzotriazole-assisted Katritzky method. The majority of those compounds were found to be selective 5-HT(2A)/5-HT(1A) receptor ligands, though less potent than their previously described pyrimidine counterparts. In particular, the three compounds 6-8 showed the highest 5-HT(2A) receptor affinity (K(i) = 34-78 nM) and were classified as 5-HT(2A) antagonists in in vivo experiments. The influence of the structural modifications on the in vitro results was discussed; however, the elucidation of the role of the central core system requires further studies.

Cu(ii)-catalyzed annulation of α,β-unsaturated ketoxime acetates with 3-formylchromones for the synthesis of functionalized 2,4-diarylpyridines

“…1, these compounds are present in numerous important biological classes of molecules, including topoisomerase inhibitors, 9 estrogen receptor ligands, 10 MNK1 inhibitors, 11 A 2A adenosine receptor antagonists, 12 and serotonin-5-HT 2A receptor ligands. 13 They possess vasodilation potency 14 and exhibit anti-inflammatory properties. 15 Various methods have been proposed for the synthesis of 2,4-diarylpyridines.…”

Highly Selective Synthesis of 2-Amino-4,6-diarylpyridine Derivatives by the Cascade Reaction of 1,1-Enediamines with α,β-Unsaturated Ketones

“…Until now, various protocols have been developed to synthesize aryl-substituted 2-aminopyridines. − The classic method to obtain this compound is transition-metal-catalyzed amination of aryl halides, typically including palladium-catalyzed Buchwald–Hartwig amination and copper-catalyzed Ullmann-type amination . Among them, 2-amino-4,6-diarylpyridine derivatives (ADPDs) are important due to their interesting biological characteristics such as A 2A adenosine receptor antagonist, serotonin-5-HT2A receptor, vasodilation potency, and anti-inflammatory agent (Figure ). As a result, various methods for ADPD synthesis have been developed.…”

Fe(OTf)3-catalyzed annulation of α,β-unsaturated ketoxime acetates with enaminones for the synthesis of functionalized 2,4-diarylpyridines

“…These compounds are present in many important biological molecules (Fig. 1), such as topoisomerase inhibitors, 10 serotonin-5-HT 2A receptors, 11 A 2A adenosine receptor antagonists, 12 MNK1 inhibitors, anti-asthma drugs, vasodilatory drugs, and anti-inflammatory agents. 13–15 Thus, various methods have been proposed to synthesize 2,4-diarylpyridines.…”