Novel Cyclic Endomorphin Analogues with Multiple Modifications and Oligoarginine Vector Exhibit Potent Antinociception with Reduced Opioid-like Side Effects

Abstract

Endomorphins (EMs) are potent pharmaceuticals for the treatment of pain. Herein, we investigated several novel EM analogues with multiple modifications and oligoarginine conjugation. Our results showed that analogues 1–6 behaved as potent μ-opioid agonists and enhanced stability and lipophilicity. Analogues 5 and 6 administered centrally and peripherally induced significant and prolonged antinociceptive effects in acute pain. Both analogues also produced long-acting antiallodynic effects against neuropathic and inflammatory pain. Furthermore, they showed a reduced acute antinociceptive tolerance. Analogue 6 decreased the extent of chronic antinociceptive tolerance, and analogue 5 exhibited no tolerance at the supraspinal level. Particularly, they displayed nontolerance-forming antinociception at the peripheral level. In addition, analogues 5 and 6 exhibited reduced or no opioid-like side effects on gastrointestinal transit, conditioned place preference (CPP), and motor impairment. The present investigation established that multiple modifications and oligoarginine-vector conjugation of EMs would be helpful in developing novel analgesics with fewer side effects.

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

“…Substituting Tyr 1 with Dmt 1 ( 1 ) increased the lipophilicity and bulkiness of the side chain, resulting in a slight (<10-fold) increase in potency at MOR and DOR but partial agonism at KOR. This result aligns with previous reports indicating that replacing Tyr 1 with Dmt in a linear or cyclic opioid peptide enhanced binding affinity and agonistic activity toward MOR and DOR. ,, …”

“…This result aligns with previous reports indicating that replacing Tyr 1 with Dmt in a linear or cyclic opioid peptide enhanced binding affinity and agonistic activity toward MOR and DOR. 17,28,32 The introduction of methyl (Ala, 2) and dimethyl side chains (Aib, 4) for Gly 3 substitutions slightly increased the potency of MOR but reduced agonistic potencies at KOR and DOR. The configuration inversion (D-Ala, 3) of the Alacontaining analog produced a slight reduction in MOR potency and resulted in poor agonistic activity at KOR and DOR.…”

“…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. 28 In this study, we developed a series of novel cyclic hexapeptide analogs by single amino acid substitution at Tyr 1 , Gly 3 , Phe 4 , or D-Pro 6 of the lead compound (0). The present study was performed to characterize the in vitro functional activity, antinociceptive activity, and metabolic stability of these new cyclic hexapeptide analogs with the objective of investigating the systematic structure−activity relationship (SAR) of compound 0 and developing new multifunctional opioids with clinical potential.…”

“…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 …”

Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery

“…However, their low ability to penetrate the BBB and low metabolic stability prohibit therapeutic uses as analgesics, and therefore significant efforts have been made to improve metabolic stability and to obtain longer lasting antinociceptive effects through various modifications [ 26 , 27 ]. Cyclic EM-1 analogs such as ZH853 (Tyr-c[ D Lys-Trp-Phe-Glu]-Gly-NH 2 ) are recent discoveries showing longer duration of action and effective antinociception in multiple pain models with reduced adverse side effects [ 28 , 29 , 30 ].…”