Discovery of 2-(3,4-dichlorophenoxy)-N-(2-morpholin-4-ylethyl)acetamide: A selective σ1 receptor ligand with antinociceptive effect

Abstract Compound 2-(3,4-dichlorophenoxy)- N -(2-morpholin-4-ylethyl)acetamide ( 1 ) was designed, prepared and the in vitro binding evaluation against σ 1 and σ 2 receptors was measured. Compound 1 showed high σ 1 receptor affinity ( K i  = 42 nM) and it was 36-times more selective for σ 1 than σ 2 receptor. Also, it was performed a molecular docking of compound 1 into the ligand binding pocket homology model of σ 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 μg/paw) and intrathecal (100 μg/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.