Arizona Health Sciences

Discovery of 5-substituted tetrahydronaphthalen-2yl-methyl with N-phenyl-N-(piperidin-4-yl)propionamide derivatives as potent opioid receptor ligands.

TitleDiscovery of 5-substituted tetrahydronaphthalen-2yl-methyl with N-phenyl-N-(piperidin-4-yl)propionamide derivatives as potent opioid receptor ligands.
Publication TypeJournal Article
Year of Publication2015
AuthorsDeekonda S, Wugalter L, Kulkarni V, Rankin D, Largent-Milnes TM, Davis P, BassiriRad NM, Lai J, Vanderah TW, Porreca F, Hruby VJ
JournalBioorg Med Chem
Volume23
Issue18
Pagination6185-94
Date Published2015 Sep 15
ISSN1464-3391
KeywordsAmides, Analgesics, Opioid, Animals, Behavior, Animal, Drug Evaluation, Preclinical, Half-Life, Ligands, Male, Narcotic Antagonists, Protein Binding, Rats, Rats, Sprague-Dawley, Receptors, Opioid, Receptors, Opioid, delta, Receptors, Opioid, mu
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.

DOI10.1016/j.bmc.2015.07.071
Alternate JournalBioorg. Med. Chem.
PubMed ID26299827
PubMed Central IDPMC4642887
Grant ListP01 DA006284 / DA / NIDA NIH HHS / United States
R01 DA013449 / DA / NIDA NIH HHS / United States
2P01 DA006284 / DA / NIDA NIH HHS / United States
314450 / / PHS HHS / United States
Faculty Member Reference: 
Tally Largent-Milnes, Ph.D.
Frank Porreca, PhD
Todd Vanderah, PhD