Assessment of substitution in the second pharmacophore of Dmt-Tic analogues

Bioorg Med Chem Lett. 2000 Dec 18;10(24):2745-8. doi: 10.1016/s0960-894x(00)00569-2.

Abstract

The Dmt-Tic pharmacophore exhibits potent delta-opioid receptor antagonism. Analogues with substitutions in the second pharmacophore with (1, 1') or without a COOH function (2-9) were synthesized: several had high delta affinity (1', 2, 7, and 9), but exhibited low to non-selectivity toward mu receptors similar to H-Dmt-Tic-amide and H-Dmt-Tic-ol. Functional bioactivity indicated high delta antagonism (pA2 7.4-7.9) (1', 2, and 9) and modest mu agonism, pEC50 (6.1-6.3) (1', 2, 8, and 9), but with Emax values analogous to dermorphin. These Dmt-Tic analogues with mixed delta antagonist/mu agonist properties would appear to be better candidates as analgesics than pure mu agonists.

Publication types

  • Comparative Study

MeSH terms

  • Analgesics / chemical synthesis*
  • Analgesics / metabolism
  • Animals
  • Binding, Competitive
  • Dipeptides / chemical synthesis
  • Dipeptides / pharmacology*
  • Guinea Pigs
  • Inhibitory Concentration 50
  • Isoquinolines / chemical synthesis
  • Isoquinolines / metabolism*
  • Mice
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / antagonists & inhibitors
  • Receptors, Opioid, mu / metabolism
  • Structure-Activity Relationship
  • Tetrahydroisoquinolines*
  • Tyrosine / analogs & derivatives*
  • Tyrosine / chemical synthesis
  • Tyrosine / metabolism*

Substances

  • Analgesics
  • Dipeptides
  • Isoquinolines
  • Receptors, Opioid, mu
  • Tetrahydroisoquinolines
  • 2',6'-dimethyltyrosine
  • 1,2,3,4-tetrahydroisoquinoline carboxylic acid
  • Tyrosine