[l-Ala3]DPDPE: A New Enkephalin Analog with a Unique Opioid Receptor Activity Profile. Further Evidence of δ-Opioid Receptor Multiplicity

Ronald C. Haaseth, Peter J. Horan, Edward J. Bilsky, Peg Davis, Teresa Zalewska, Jirina Slaninova, Henry I. Yamamura, Steven J. Weber, Thomas P. Davis, Frank Porreca, Victor J. Hruby

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

To investigate δ-opioid receptor topography near the 3-position of [D-Pen2,D-Pen5]enkephalin (DPDPE), a series of small-group 3-position analogs of DPDPE have been synthesized and assayed for binding potencies and in vitro biological activities. l-Amino acid substitutions at this position are highly favored over D-amino acid substitutions, with the smallest, [l-Ala3]DPDPE (DPADPE), being the most favored in the series investigated, [l-Ala3] DPDPE is nearly δ-potent and more δ-selective in both rat brain binding (18 nM vs [3H] [p-CIPhe4]DPDPE and μ/δ = 610) and peripheral bioassays (12 nM in the MVD and GPI/MVD = 4500) when compared to DPDPE (8.5 nM, μ/δ = 73 and 4.1 nM, GPI/MVD = 1800, respectively). Whereas DPDPE is a potent analgesic when given icv, [l-Ala3] DPDPE is only a weak analgesic. However, [l-Ala3] DPDPE has been found to antagonize DPDPE, but not Deltorphin II, in a moderately potent (pA2 = 5.7) and selective fashion in vivo. Thus, [l-Ala3] DPDPE is a fairly potent agonist at peripheral δ receptors and is a moderately potent (mixed) antagonist of δ1 receptors in the brain. It appears that [l-Ala3]DPDPE does not interact in any significant manner with δ2 or μ receptors in the brain.

Original languageEnglish (US)
Pages (from-to)1572-1577
Number of pages6
JournalJournal of Medicinal Chemistry
Volume37
Issue number11
DOIs
StatePublished - May 1 1994

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of '[l-Ala<sup>3</sup>]DPDPE: A New Enkephalin Analog with a Unique Opioid Receptor Activity Profile. Further Evidence of δ-Opioid Receptor Multiplicity'. Together they form a unique fingerprint.

  • Cite this