Multitargeted Opioid Ligand Discovery as a Strategy to Retain Analgesia and Reduce Opioid-Related Adverse Effects

Abstract

The global “opioid crisis” has placed enormous pressure on the opioid ligand discovery community to produce novel opioid analgesics with superior opioid-related adverse-effect profiles compared with morphine. In this Perspective, the multitargeted opioid ligand strategy for the discovery of opioid analgesics with superior preclinical therapeutic indices relative to morphine is reviewed and discussed. Dual-targeted μ-opioid (MOP)/δ-opioid (DOP) ligands in which the in vitro DOP antagonist potency at least equals that of the MOP agonist activity, and are devoid of DOP or κ-opioid (KOP) agonist activity, are sufficiently promising candidates to warrant further investigation. Dual-targeted MOP/NOP partial agonists have superior preclinical therapeutic indices to morphine and/or fentanyl in nonhuman primates and are also considered promising. Based on the poor preclinical and clinical therapeutic indices of cebranopadol, which is a full agonist at MOP, DOP, and NOP receptors and a partial agonist at the KOP receptor, this pharmacologic template should be avoided.

Structure–Activity Relationships of a Novel Cyclic Hexapeptide That Exhibits Multifunctional Opioid Agonism and Produces Potent Antinociceptive Activity

“…This finding suggests that the length of the aromatic side chain in the Phe 4 residue may be optimal for interaction with opioid receptors, which is consistent with the results obtained from the length modification of the Phe 4 side chain in cyclic EM-2 analogs. 27 Analog 15, which added an electron-withdrawing fluorine group at the para position of Phe 4 , showed strong agonistic activity at all three opioid receptors, with a 34-fold increase in potency for MOR, a 31fold increase in potency for KOR, and a 3.5-fold increase in potency for DOR compared to 0. By contrast, adding an electron-donating methyl group at the para position of the phenyl ring (16) maintained strong potency at MOR but acted as a partial agonist at KOR and had a 10-fold decrease in potency at DOR.…”

“…23 Substituting Phe 4 with D-1/2-naphthyl-3alanine, 2′, 3′, or 4′-methyl phenylalanine or fluorinated phenylalanine in the cyclic peptide Dmt-c[D-Lys-Phe-Phe-Asp]-NH 2 preserved or even improved affinities for both MOR and DOR. 24−26 However, replacing Phe 4 of the cyclic peptide Tyr-c[D-Lys-Phe-Phe-Asp]-NH 2 with β 3 -Phe, Homo-Phe, β 3 -Homo-Phe, and Phg did not yield more potent cyclopeptides than the parent compound. 27 Generally, replacing the Phe 4 residue with an aliphatic hydrophobic moiety improves the MOR selectivity of enkephalin analogs by significantly reducing potency at DOR.…”

“…24−26 However, replacing Phe 4 of the cyclic peptide Tyr-c[D-Lys-Phe-Phe-Asp]-NH 2 with β 3 -Phe, Homo-Phe, β 3 -Homo-Phe, and Phg did not yield more potent cyclopeptides than the parent compound. 27 Generally, replacing the Phe 4 residue with an aliphatic hydrophobic moiety improves the MOR selectivity of enkephalin analogs by significantly reducing potency at DOR. 14 Taken together, exploring the effects of Tyr 1 , Gly 3 , and Phe 4 residues with different modifications on opioid bioactivity will be helpful to facilitate the rational design of multifunctional opioid receptor ligands with different potencies and selectivities.…”

“…27 Generally, replacing the Phe 4 residue with an aliphatic hydrophobic moiety improves the MOR selectivity of enkephalin analogs by significantly reducing potency at DOR. 14 Taken together, exploring the effects of Tyr 1 , Gly 3 , and Phe 4 residues with different modifications on opioid bioactivity will be helpful to facilitate the rational design of multifunctional opioid receptor ligands with different potencies and selectivities. In addition, employing various chemical modifications such as cyclization, substitution of Tyr 1 with Dmt, para-chlorination of Phe 4 , and C-terminal oligoarginine-vector conjugation produced several new EM analogs with high opioid affinities and pharmacological activities, behaving as potent MOR agonists.…”

seco-1-Azacubane-2-carboxylic Acid: Derivative Scope and Comparative Biological Evaluation

“…29 Although the incorporation of 1 in the selected examples led to reduced activity, the observed increased DOP activity with the endomorphin derivative 21 provides encouragement that 1 may find future application as a strained non-natural amino acid, 30 e.g., offering insight into the development of multitargeted opioid receptor ligands. 31…”