Phenylalanine Stereoisomers of CJ-15,208 and [d-Trp]CJ-15,208 Exhibit Distinctly Different Opioid Activity Profiles.

Ariana C Brice-Tutt,Jay P Mclaughlin,Thomas F Murray,Shainnel O Eans,Tanvir Khaliq,Michelle L Ganno,Sanjeewa N Senadheera,Jane V Aldrich

doi:10.3390/molecules25173999

Abstract

The macrocyclic tetrapeptide cyclo[Phe-d-Pro-Phe-Trp] (CJ-15,208) and its stereoisomer cyclo[Phe-d-Pro-Phe-d-Trp] exhibit different opioid activity profiles in vivo. The present study evaluated the influence of the Phe residues’ stereochemistry on the peptides’ opioid activity. Five stereoisomers were synthesized by a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, and for opioid activity and selectivity in vivo in the mouse 55 °C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance development, and place conditioning were also assessed in vivo. All of the stereoisomers exhibited antinociception following either intracerebroventricular or oral administration differentially mediated by multiple opioid receptors, with kappa opioid receptor (KOR) activity contributing for all of the peptides. However, unlike the parent peptides, KOR antagonism was exhibited by only one stereoisomer, while another isomer produced DOR antagonism. The stereoisomers of CJ-15,208 lacked significant respiratory effects, while the [d-Trp]CJ-15,208 stereoisomers did not elicit antinociceptive tolerance. Two isomers, cyclo[d-Phe-d-Pro-d-Phe-Trp] (3) and cyclo[Phe-d-Pro-d-Phe-d-Trp] (5), did not elicit either preference or aversion in a conditioned place preference assay. Collectively, these stereoisomers represent new lead compounds for further investigation in the development of safer opioid analgesics.

Highlights

The endogenous opioid system is a valuable therapeutic target for the treatment of pain as it is extensively involved in pain perception and experience [1]
The stereoisomers of CJ-15,208 and its d-Trp isomer (Figure 1) were synthesized by a combination of solid phase synthesis of the linear precursors followed by cyclization in solution using modifications to our original strategy [20,22] to improve the yields of the macrocyclic peptides
CJ-15,208 is structurally distinct from the endogenous opioid peptides, The macrocyclictetrapeptide tetrapeptide

Summary

Introduction

The endogenous opioid system is a valuable therapeutic target for the treatment of pain as it is extensively involved in pain perception and experience [1]. The majority of opioid ligands used clinically for the treatment of pain are mu-opioid receptor (MOR) agonists, agonists of kappa (KOR) and delta (DOR) receptors produce analgesia. Molecules 2020, 25, 3999 produce a number of undesirable opioid-related side effects that complicate their therapeutic utility. MOR-selective agonists are reinforcing, and produce analgesic tolerance and respiratory depression [2]. KOR selective agonists produce dysphoria, sedation, and psychotomimetic effects [3], while DOR-selective agonists can induce seizure activity [4]. Multifunctional opioids, ligands with mixed agonist and/or antagonist activity at one or more opioid receptor, have demonstrated potent antinociception, possibly due to synergistic effects [5]

Methods

Results

Conclusion