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

Considering the interesting pharmacological profile of the delta (?) 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 ? opioid receptor binding affinity. Depending upon the substituents on the diazatricyclodecane ring, these compounds displayed varying selectivity for ? opioid receptor over ? and ? receptors. Amongst the novel compounds, 1Aa showed the more interesting biological profile, with higher ? affinity and selectivity compared to SNC-80. The ? receptor agonist profile and antinociceptive activity of 1Aa were confirmed using ex-vivo (isolated mouse vas deferens) and in vivo (tail flick) assays. © 2013 Elsevier Masson SAS. All rights reserved.