Synthesis and biological evaluation of novel delta (δ) opioid receptor ligands with diazatricyclodecane skeletons

Eur J Med Chem. 2013 Nov:69:413-26. doi: 10.1016/j.ejmech.2013.09.014. Epub 2013 Sep 19.

Abstract

Considering the interesting pharmacological profile of the delta (δ) selective opioid agonist compound SNC-80, conformationally constrained analogs containing two diazatricyclodecane ring systems in place of dimethylpiperazine core motif were synthesized. The compounds showed subnanomolar or low nanomolar δ opioid receptor binding affinity. Depending upon the substituents on the diazatricyclodecane ring, these compounds displayed varying selectivity for δ opioid receptor over μ and κ receptors. Amongst the novel compounds, 1Aa showed the more interesting biological profile, with higher δ affinity and selectivity compared to SNC-80. The δ receptor agonist profile and antinociceptive activity of 1Aa were confirmed using ex-vivo (isolated mouse vas deferens) and in vivo (tail flick) assays.

Keywords: 2,7-Diazatricyclo[4.4.0.0(3,8)]decane; 9,10-Diazatricyclo[4.2.1.1(2,5)]decane; Antinociceptive activity; Binding assays; δ-Agonist SNC-80; δ-Opioid receptor ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / administration & dosage
  • Analgesics / chemical synthesis
  • Analgesics / pharmacology*
  • Animals
  • Dose-Response Relationship, Drug
  • Ligands
  • Mice
  • Molecular Structure
  • Pain / drug therapy*
  • Pain Measurement
  • Polycyclic Compounds / administration & dosage
  • Polycyclic Compounds / chemical synthesis
  • Polycyclic Compounds / pharmacology*
  • Receptors, Opioid, delta / agonists*
  • Structure-Activity Relationship

Substances

  • 4-((10-allyl-9,10-diazatricyclo(4.2.1.12,5)dec-9-yl)-(3-methoxyphenyl)methyl)-N,N-diethylbenzamide
  • Analgesics
  • Ligands
  • Polycyclic Compounds
  • Receptors, Opioid, delta