A Novel Approach to Safer Analgesics: Mu Opioid Receptor Agonist & Delta Opioid Receptor Antagonist Peptidomimetics

Opioid analgesics exert their therapeutic and unwanted effects by activation of the mu‐opioid receptor (MOR). Repeated administration of opioid analgesics and subsequent chronic MOR activation promotes opioid tolerance and physical dependence. It has been proposed that activation of MOR with concurrent antagonism of the delta‐opioid receptor (DOR) can attenuate the development of opioid tolerance and dependence. To further investigate the utilization of concurrent MOR agonism and DOR antagonism we designed, synthesized, and characterized a library of “peptidomimetics” that have elements of opioid peptides vital for activity but retain small molecule‐like features necessary for blood‐brain‐barrier penetration. Compounds were evaluated in membrane preparations of cloned cell lines expressing either MOR, DOR, or kappa‐opioid receptors (KOR). [ 35 S]‐GTPγS binding to measure G protein‐coupled activation was used. Full agonists at each opioid receptor (DAMGO, DPDPE, and U69,593, respectively) were employed as standards. Maximum binding and potency (EC 50 ) values were determined from concentration‐effect curves. To measure affinity (K i ) values, competition binding using [ 3 H]‐diprenorphine was performed. Peptidomimetics that demonstrated promising bi‐functional activity were tested for antinociceptive activity in vivo . Compared to repeated morphine‐treated mice, repeated peptidomimetic treated mice developed less analgesic tolerance or physical dependence. Analysis of in vitro and in vivo data has permitted structure‐activity relationships to guide further chemical synthesis and the discovery of opioid analgesics that may have improved clinical utility. Support or Funding Information Supported by DA‐03910 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .