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

• Synthesis of conformationally restricted analogs of δ-agonist SNC-80 was reported.
• High δ affinity and selectivity were observed for most of the compounds synthesized.
• Preliminary in vivo assays confirmed antinociceptive activity of 1Aa in tail flick test.

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.

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