title: Design synthesis and structure-activity relationship of 5-substituted (tetrahydronaphthalen-2yl)methyl with N-phenyl-N-(piperidin-2-yl)propionamide derivatives as opioid ligands.
abstract: Here, we report the design, synthesis and structure activity relationship of novel small molecule opioid ligands based on 5-amino substituted (tetrahydronaphthalen-2-yl)methyl moiety with N-phenyl-N-(piperidin-2-yl)propionamide derivatives. We synthesized various molecules including amino, amide and hydroxy substitution on the 5th position of the (tetrahydronaphthalen-2-yl)methyl moiety. In our further designs we replaced the (tetrahydronaphthalen-2-yl)methyl moiety with benzyl and phenethyl moiety. These N-phenyl-N-(piperidin-2-yl)propionamide analogues showed moderate to good binding affinities (850-4 nM) and were selective towards the μ opioid receptor over the δ opioid receptors. From the structure activity relationship studies, we found that a hydroxyl substitution at the 5th position of (tetrahydronapthalen-2yl)methyl group, ligands 19 and 20, showed excellent binding affinities 4 and 5 nM, respectively, and 1000 fold selectivity towards the μ opioid relative to the delta opioid receptor. The ligand 19 showed potent agonist activities 75±21 nM, and 190±42 nM in the GPI and MVD assays. Surprisingly the fluoro analogue 20 showed good agonist activities in MVD assays 170±42 nM, in contrast to its binding affinity results.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, 1306 E. University Boulevard, Tucson, AZ 85721, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Deekonda
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: David
authors.initials: D
authors.lastname: Rankin
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Peg
authors.initials: P
authors.lastname: Davis
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Porecca
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, 1306 E. University Boulevard, Tucson, AZ 85721, USA. Electronic address: hruby@email.arizona.edu.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000701:Analgesics, Opioid; D008024:Ligands; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C034666:propionamide
keywords: N-Phenyl-N-(piperidin-2-yl)propionamide; Opioid receptors; Opioids; Pain