Development of compounds with mu‐opioid agonism and delta‐opioid antagonism as novel analgesics

Opioid analgesics exert both their beneficial and unwanted effects by activation of the mu‐opioid receptor (MOPR). Furthermore, repeated administration of opioid analgesics and subsequent chronic MOPR activation leads to opioid tolerance and physical dependence. Many attempts to eliminate the adverse effects of opioids by the synthesis of more potent and selective MOPR agonists have proved to be unsuccessful. It has been proposed that activation of MOPR with concurrent antagonism of the delta‐opioid receptor (DOPR) can reduce the development of opioid tolerance and reward. Here we report on the development of “mixed efficacy compounds” that activate MOPR and inhibit DOPR. We evaluated potential mixed efficacy compounds using two in vitro assays; 1) [ 35 S]‐GTPγS binding assays to measure G protein activation in membrane preparations of cloned cell lines expressing either MOPR, DOPR, or kappa‐opioid receptors (KOPR). Full agonists at each opioid receptor (DAMGO, DPDPE, and U69,593, respectively) were used as standards for [ 35 S]‐GTPγS binding. Maximum binding and potency (EC 50 ) values of the novel compounds were determined from concentration‐effect curves. 2) Competition binding assays using [ 3 H]‐diprenorphine (opioid antagonist) to determine affinity (K i ) values. Comparison of affinity and degree of agonism of the novel compounds at MOPR and DOPR revealed structure‐activity relationships to guide further chemical modification and drug development to improve compounds devoid of tolerance and dependence liabilities. Support or Funding Information Supported by DA‐03910