title: Discovery of 5-substituted tetrahydronaphthalen-2yl-methyl with N-phenyl-N-(piperidin-4-yl)propionamide derivatives as potent opioid receptor ligands.
abstract: A new series of novel opioid ligands have been designed and synthesized based on the 4-anilidopiperidine scaffold containing a 5-substituted tetrahydronaphthalen-2yl)methyl group with different N-phenyl-N-(piperidin-4-yl)propionamide derivatives to study the biological effects of these substituents on μ and δ opioid receptor interactions. Recently our group reported novel 4-anilidopiperidine analogues, in which several aromatic ring-contained amino acids were conjugated with N-phenyl-N-(piperidin-4-yl)propionamide and examined their biological activities at the μ and δ opioid receptors. In continuation of our efforts in these novel 4-anilidopiperidine analogues, we took a peptidomimetic approach in the present design, in which we substituted aromatic amino acids with tetrahydronaphthalen-2yl methyl moiety with amino, amide and hydroxyl substitutions at the 5th position. In in vitro assays these ligands, showed very good binding affinity and highly selective toward the μ opioid receptor. Among these, the lead ligand 20 showed excellent binding affinity (2 nM) and 5000 fold selectivity toward the μ opioid receptor, as well as functional selectivity in GPI assays (55.20 ± 4.30 nM) and weak or no agonist activities in MVD assays. Based on the in vitro bioassay results the lead compound 20 was chosen for in vivo assessment for efficacy in naïve rats after intrathecal administration. Compound 20 was not significantly effective in alleviating acute pain. This discrepancy between high in vitro binding affinity, moderate in vitro activity, and low in vivo activity may reflect differences in pharmacodynamics (i.e., engaging signaling pathways) or pharmacokinetics (i.e., metabolic stability). In sum, our data suggest that further optimization of this compound 20 is required to enhance in vivo activity.
authors: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA.
authors: Srinivas
authors: S
authors: Deekonda
authors: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA.
authors: Lauren
authors: L
authors: Wugalter
authors: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA.
authors: Vinod
authors: V
authors: Kulkarni
authors: Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA.
authors: David
authors: D
authors: Rankin
authors: Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA.
authors: Tally M
authors: TM
authors: Largent-Milnes
authors: Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA.
authors: Peg
authors: P
authors: Davis
authors: Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA.
authors: Neemah M
authors: NM
authors: Bassirirad
authors: Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA.
authors: Josephine
authors: J
authors: Lai
authors: Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA.
authors: Todd W
authors: TW
authors: Vanderah
authors: Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA.
authors: Frank
authors: F
authors: Porreca
authors: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA. Electronic address: hruby@email.arizona.edu.
authors: Victor J
authors: VJ
authors: Hruby
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D008024:Ligands; D008297:Male; D009292:Narcotic Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000737:chemistry* / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000737:chemistry / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000737:chemistry / Q000378:metabolism
chemical_list: D000577:Amides; D000701:Analgesics, Opioid; D008024:Ligands; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C034666:propionamide
keywords: 4-Anilidopiperidines; Opioid receptors; Opioids; Pain