Biological and conformational evaluation of bifunctional compounds for opioid receptor agonists and neurokinin 1 receptor antagonists possessing two penicillamines

Takashi Yamamoto, Padma Nair, Neil E. Jacobsen, Vinod Kulkarni, Peg Davis, Shou Wu Ma, Edita Navratilova, Henry I. Yamamura, Todd W. Vanderah, Frank Porreca, Josephine Lai, Victor J. Hruby

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Neuropathic pain states and tolerance to opioids can result from system changes in the CNS, such as up-regulation of the NK1 receptor and substance P, lead to antiopioid effects in ascending or descending pain-signaling pathways. Bifunctional compounds, possessing both the NK1 antagonist pharmacophore and the opioid agonist pharmacophore with ?-selectivity, could counteract these system changes to have significant analgesic efficacy without undesirable side effects. As a result of the introduction of cyclic and topological constraints with penicillamines, 2 (Tyr-cyclo[d-Pen-Gly-Phe-Pen]-Pro-Leu-Trp-NH-[3?,5?-(CF 3)2-Bzl]) was found as the best bifunctional compound with effective NK1 antagonist and potent opioid agonist activities, and 1400-fold ?-selectivity over the ?-receptor. The NMR structural analysis of 2 revealed that the relative positioning of the two connected pharmacophores as well as its cyclic and topological constraints might be responsible for its excellent bifunctional activities as well as its significant ?-opioid selectivity. Together with the observed high metabolic stability, 2 could be considered as a valuable research tool and possibly a promising candidate for a novel analgesic drug.

Original languageEnglish (US)
Pages (from-to)5491-5501
Number of pages11
JournalJournal of Medicinal Chemistry
Volume53
Issue number15
DOIs
StatePublished - Aug 12 2010

    Fingerprint

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this