PeripherallyRestricted Fused Heterocyclic PeptidomimeticMultifunctional Opioid Agonists as Novel, Potent Analgesics

Heterocyclic peptidomimetics are constrained compounds that mimic the biological efficacy of peptides while offering increased stability. We have previously generated a diazaheterocyclic peripherally selective, mixed-opioid agonist peptidomimetic that produced synergistic antinociception with decreased side effects. Working from two earlier templates, we report here the synthesis of 15 new diazaheterocyclic analogues. In vitro screening with radioligand competition binding assays and [³⁵S]GTPγS assays demonstrated variable affinity for and activity at μ (MOR), δ (DOR), and κ (KOR) opioid receptors across the series, with three (<b>2663</b>-<b>48</b>, <b>2638</b>-<b>28</b> and <b>2638</b>-<b>33</b>) displaying good affinity for DOR and/or KOR. All three compounds produced dose-dependent, opioid-receptor mediated antinociception in the mouse 55 °C warm-water tail-withdrawal and acetic-acid writhing assay, although a ratio of ED₅₀ values in these assays suggested poor BBB penetration by <b>2638</b>-<b>33</b>; results confirmed by testing with naloxone-methiodide. The data suggest these diazaheterocyclic mixed-activity, peripherally restricted opioid receptor agonists may hold potential as new, safer analgesics.