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

Srinivas Deekonda, Lauren Wugalter, Vinod Kulkarni, David Rankin, Tally M. Largent-Milnes, Peg Davis, Neemah M. Bassirirad, Josephine Lai, Todd W Vanderah, Frank Porreca, Victor J Hruby

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)6185-6194
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number18
DOIs
StatePublished - Sep 15 2015

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Opioid Receptors
Ligands
Derivatives
Assays
Pharmacodynamics
Peptidomimetics
Lead compounds
Aromatic Amino Acids
Pharmacokinetics
Bioassay
Acute Pain
Bioactivity
Scaffolds
Amides
Biological Assay
Hydroxyl Radical
Opioid Analgesics
Rats
Substitution reactions
Amino Acids

Keywords

  • 4-Anilidopiperidines
  • Opioid receptors
  • Opioids
  • Pain

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Discovery of 5-substituted tetrahydronaphthalen-2yl-methyl with N-phenyl-N-(piperidin-4-yl)propionamide derivatives as potent opioid receptor ligands. / Deekonda, Srinivas; Wugalter, Lauren; Kulkarni, Vinod; Rankin, David; Largent-Milnes, Tally M.; Davis, Peg; Bassirirad, Neemah M.; Lai, Josephine; Vanderah, Todd W; Porreca, Frank; Hruby, Victor J.

In: Bioorganic and Medicinal Chemistry, Vol. 23, No. 18, 15.09.2015, p. 6185-6194.

Research output: Contribution to journalArticle

Deekonda, Srinivas ; Wugalter, Lauren ; Kulkarni, Vinod ; Rankin, David ; Largent-Milnes, Tally M. ; Davis, Peg ; Bassirirad, Neemah M. ; Lai, Josephine ; Vanderah, Todd W ; Porreca, Frank ; Hruby, Victor J. / Discovery of 5-substituted tetrahydronaphthalen-2yl-methyl with N-phenyl-N-(piperidin-4-yl)propionamide derivatives as potent opioid receptor ligands. In: Bioorganic and Medicinal Chemistry. 2015 ; Vol. 23, No. 18. pp. 6185-6194.
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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 na{\"i}ve 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.",
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