Discovery of Novel Lead in the Group of N-substituted Piperazine Ether Derivatives with Potential Histamine H₃ Receptor Activity

Abstract

The search for novel lead from the group of various substituted N-piperazine ether derivatives was performed. Acyl- and pyridylpiperazine ethyl/propyl ethers were obtained via three different synthetic pathways. Affinity to histamine H3 receptor was established, as well as, for selected compounds, selectivity towards histamine H4R. Docking studies to the histamine H3R homology model strengthened the position of (4-(3-(4-(3-chlorobenzoyl)piperazin-1- yl)propoxy)phenyl)(cyclopropyl)methanone (compound 26) as a novel lead for further studies on histamine H3 receptor antagonist/inverse agonist.

Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist

“…The reaction was stirred for 24 h, slowly warming to rt. The reaction was adsorbed onto silica gel (2 g) and purified by silica chromatography to afford the previously reported acylated product as a white solid (818 mg, 2.72 mmol, 68% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 2.42–2.66 (m, 4H), 2.59 (t, J = 5.3 Hz, 2H), 3.46–3.79 (m, 4H), 3.65 (t, J = 5.4 Hz, 2H), 3.84 (s, 3H), 6.91 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H); 13 C NMR (126 MHz, CDCl 3 ) δ 53.0 (br), 55.4, 57.8, 59.3, 113.7, 127.7, 129.2, 160.8, 170.3; HRMS ( m / z ): calcd for C 14 H 21 N 2 O 3 [M + H] + 265.1547; found 265.1575.…”

“…The reaction was stirred for 24 h, slowly warming to rt. The reaction was adsorbed onto silica gel (2 g) and purified by silica chromatography to afford the previously reported acylated product 89 as a white solid (818 mg, 2.72 mmol, 68% yield). 1 (40 mL) were added HOBt (314 mg, 2.32 mmol, 1.0 equiv) and EDC•HCl (445 mg, 2.32 mmol, 1.0 equiv), and the reaction was stirred at rt for 10 min.…”

Pharmacological andSARanalysis of theLINS01 compounds at the human histamine H1, H2, and H3receptors

“…Several H 3 R ligands reported in the literature present the N ‐arylpiperazine moiety such as DL‐80 which presents medium to low affinity to H 3 R, but with certain selectivity over H 4 R. However, these compounds present a longer linker than the LINS01 compounds, and thus, the position of the most basic nitrogen changes accordingly. Docking studies suggest that a salt bridge between a basic nitrogen and Glu206 is a key interaction to the antagonist activity.…”