Design, Synthesis, and Pharmacological Characterization of Novel Endomorphin-1 Analogues as Extremely Potent μ-Opioid Agonists

Abstract

Recently we reported the synthesis and structure-activity study of endomorphin-1 (EM-1) analogues containing novel, unnatural α-methylene-β-aminopropanoic acids (Map). In the present study, we describe new EM-1 analogues containing Dmt(1), (R/S)-βPro(2), and (ph)Map(4)/(2-furyl)Map(4). All of the analogues showed a high affinity for the μ-opioid receptor (MOR) and increased stability in mouse brain homogenates. Of the new compounds, Dmt(1)-(R)-βPro(2)-Trp(3)-(2-furyl)Map(4) (analogue 12) displayed the highest affinity toward MOR, in the picomolar range (Ki(μ) = 3.72 pM). Forskolin-induced cAMP accumulation assays indicated that this analogue displayed an extremely high agonistic potency, in the subpicomolar range (EC50 = 0.0421 pM, Emax = 99.5%). This compound also displayed stronger in vivo antinociceptive activity after iv administration when compared to morphine in the tail-flick test, which indicates that this analogue was able to cross the blood-brain barrier.

Endomorphin analog exhibited superiority in alleviating neuropathic hyperalgesia via weak activation of NMDA receptors

“…MEL-0614 is an EM-1 analog that is highly selective and agonistic for the μ-opioid receptor. In addition to its powerful analgesic effect, it also shows few toxic side effects (Liu, Wang, & Xing, 2013b); thus we chose this analog for subsequent hyperalgesia studies.…”

Endomorphin-1 analogues (MELs) penetrate the blood–brain barrier and exhibit good analgesic effects with minimal side effects

“…However, the inability of EM-1 to pass through the BBB has greatly hampered its clinical development (Tomboly et al, 2002;Janecka et al, 2008;Liu and Wang, 2012). In our previous study, we described a series of EM-1 analogues (termed MELs) obtained by chemical modifications that showed improved in vitro characteristics as compared to the parent peptide Liu et al, 2013). The aim of the present investigation was to characterize and compare the actions of EM-1 and its four analogues on different animal pain models and their BBB permeability.…”

“…In the present study, EM-1 and its analogues were synthesized by manual solution-phase methods as described in our previous report Liu et al, 2013). Crude products were purified by semipreparative RP-HPLC and were 95e99% pure as determined by analytical RP-HPLC.…”

Structural and Biological Exploration of Phe3–Phe4-Modified Endomorphin-2 Peptidomimetics

“…4,5 It is well-known that the amino acid Pro represents a crucial factor in determining the structural and conformational properties of EM-2 analogues, acting as a stereochemical spacer, capable of favoring proper spatial orientation of the aromatic side chain groups. 6 In EM-2, aromatic amino acid side chains exhibit considerable conformational flexibility, especially the Phe 3 aromatic ring, which is free to adopt a bioactive conformation.…”