title: 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 σ1 and σ2 receptors was measured. Compound 1 showed high σ1 receptor affinity (Ki=42 nM) and it was 36-times more selective for σ1 than σ2 receptor. Also, it was performed a molecular docking of compound 1 into the ligand binding pocket homology model of σ1 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.
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico, Mexico. Electronic address: gabriel_navarrete@uaem.mx.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Navarrete-Vázquez
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico, Mexico.
authors.forename: Amaya
authors.initials: A
authors.lastname: Austrich-Olivares
authors.affiliation: Departamento de Sistemas Biológicos, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Xochimilco, México D.F., 04960, Mexico, Mexico.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Godínez-Chaparro
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico, Mexico.
authors.forename: Sergio
authors.initials: S
authors.lastname: Hidalgo-Figueroa
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico, Mexico.
authors.forename: Samuel
authors.initials: S
authors.lastname: Estrada-Soto
authors.affiliation: Cátedra CONACyT, Departamento de Recursos del Mar, Centro de Investigación y de Estudios Avanzados del IPN, Unidad Mérida, 97310 Yucatán, Mexico, Mexico.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Hernández-Núñez
authors.affiliation: Institute for Chemistry and Chemical Biology, Zürich University of Applied Sciences, 8820 Wädenswil, Switzerland, Switzerland; Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, D-48149 Münster, Germany, Germany.
authors.forename: Héctor
authors.initials: H
authors.lastname: Torres-Gómez
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, D-48149 Münster, Germany, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, D-48149 Münster, Germany, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000081:Acetamides / Q000737:chemistry / Q000494:pharmacology*; D000700:Analgesics / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D020134:Catalytic Domain; D005260:Female; D007278:Injections, Spinal; D008024:Ligands; D062105:Molecular Docking Simulation; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012015:Reference Standards; D000097605:Sigma-1 Receptor
chemical_list: D000081:Acetamides; D000700:Analgesics; D008024:Ligands; D009025:Morpholines; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C000613085:2-(3,4-dichlorophenoxy)-N-(2-morpholin-4-ylethyl)acetamide; C030686:acetamide
keywords: Binding assay; Formalin test; Pain; σ receptors