Biological Effects on μ-Receptors Affinity and Selectivity of Arylpropenyl Chain Structural Modification on...

Opioid analgesics are clinically used to relieve severe pain in acute postoperative and cancer pain, and also in the long term in chronic pain. The analgesic action is mediated by micro-, δ-, and κ-receptors, but currently, with few exceptions for k-agonists, micro-agonists are the only ones used in therapy. Previously synthesized compounds with diazotricyclodecane cores (DTDs) have shown their effectiveness in binding opioid receptors. Fourteen novel diazatricyclodecanes belonging to the 9-propionyl-10-substituted-9,10-diazatricyclo[4.2.1.1^2,5]decane (compounds 20-23, 53, 57 and 59) and 2-propionyl-7-substituted-2,7-diazatricyclo[4.4.0.0^3,8]decane (compounds 24-27, 54, 58 and 60) series, respectively, have been synthesized and their ability to bind to the opioid micro-, δ- and κ-receptors was evaluated. Five of these derivatives, compounds 20, 21, 24, 26 and 53, showed micro-affinity in the nanomolar range with a negligible affinity towards δ- and κ-receptors and high micro-receptor selectivity. The synthesized compounds showed micro-receptor selectivity higher than those of previously reported methylarylcinnamyl analogs.