Discovery of 2-(3,4-dichlorophenoxy)-N-(2-morpholin-4-ylethyl)acetamide: A selective sigma(1) receptor ligand with antinociceptive effect

摘要

Compound 2-(3,4-dichlorophenoxy)-N-(2-morpholin-4-ylethyl)acetamide (1) was designed, prepared and the in vitro binding evaluation against sigma(1) and sigma(2) receptors was measured. Compound 1 showed high sigma(1) receptor affinity (K-i = 42 nM) and it was 36-times more selective for sigma(1) than sigma(2) receptor. Also, it was performed a molecular docking of compound 1 into the ligand binding pocket homology model of sigma(1) receptor, showing a salt bridge between the ionized morpholine ring and Asp126, as well as important short contacts with residues Tyr120, His154 and Trp164. Ligand efficiency indexes and predicted toxicity analysis revealed an excellent intrinsic quality of 1. The antinociceptive effect of compound 1 was determined using the formalin test. The ipsilateral local peripheral (10-300 mu g/paw) and intrathecal (100 mu g/rat) administration of 1 produced a reduction in formalin-induced nociception. The in vivo results indicated that 1 may be effective in treating inflammatory pain. (C) 2016 Elsevier Masson SAS. All rights reserved.