Synthesis of 3,6-bis[H-Tyr/H-Dmt-NH(CH2)m,n]-2(1H)pyrazinone derivatives: function of alkyl chain length on opioid activity

Bioorg Med Chem Lett. 2006 Nov 15;16(22):5793-6. doi: 10.1016/j.bmcl.2006.08.079. Epub 2006 Sep 1.

Abstract

Dimeric opioid analogues linked to a pyrazinone platform, 3-[Tyr/Dmt-NH(CH2)m]-6-[Tyr/Dmt-NH(CH2)n]-2(1H)-pyrazinone (m, n=3 or 4), were synthesized. The Tyr-containing compound (m=4, n=3) exhibited mu-receptor affinity (K(i)mu; 7.58 nM) comparable to that of morphine, while the Dmt derivatives exhibited considerably higher affinity (K(i)mu; 0.021-0.051 nM) with corresponding agonism (IC50=1.79-4.93 nM). Interestingly one compound (m=4, n=3) revealed modest delta-opioid agonism; the converse analogue (m=3, n=4), however, was inactive in MVD assay.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Models, Chemical
  • Narcotic Antagonists* / chemical synthesis*
  • Narcotic Antagonists* / pharmacology
  • Pyrazines / chemical synthesis*
  • Pyrazines / pharmacology
  • Rats
  • Receptors, Opioid, delta / agonists
  • Receptors, Opioid, mu / antagonists & inhibitors
  • Tyrosine / analogs & derivatives*
  • Tyrosine / chemical synthesis
  • Tyrosine / pharmacology

Substances

  • Narcotic Antagonists
  • Pyrazines
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • Tyrosine