Design and synthesis of opioidmimetics containing 2',6'-dimethyl-L-tyrosine and a pyrazinone-ring platform

Bioorg Med Chem Lett. 2007 Nov 1;17(21):5768-71. doi: 10.1016/j.bmcl.2007.08.058. Epub 2007 Aug 28.

Abstract

Twelve 2',6'-dimethyl-L-tyrosine (Dmt) analogues linked to a pyrazinone platform were synthesized as 3- or 6-[H-Dmt-NH(CH(2))(n)],3- or 6-R-2(1H)-pyrazinone (n=1-4). 3-[H-Dmt-NH-(CH(2))(4)]-6-beta-phenethyl-5-methyl-2(1H)-pyrazinone 11 bound to mu-opioid receptors with high affinity (K(i)mu=0.13 nM; K(i)delta/K(i)mu=447) with mu-agonism (GPI IC(50)=15.9 nM) and weak delta-antagonism (MVD pA(2)=6.35). Key factors affecting opioid affinity and functional bioactivity are the length of the aminoalkyl chain linked to Dmt and the nature of the R residue. These data present a simplified method for the formation of pyrazinone opioidmimetics and new lead compounds.

Publication types

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

MeSH terms

  • Analgesics, Opioid / chemical synthesis*
  • Analgesics, Opioid / chemistry
  • Drug Design
  • Molecular Mimicry*
  • Pyrazines / chemistry*
  • Tyrosine / analogs & derivatives*
  • Tyrosine / chemistry

Substances

  • Analgesics, Opioid
  • Pyrazines
  • 2',6'-dimethyltyrosine
  • Tyrosine