Bifunctional [2‘,6‘-Dimethyl-<scp>l</scp>-tyrosine]endomorphin-2 Analogues Substituted at Position 3 with Alkylated Phenylalanine Derivatives Yield Potent Mixed μ-Agonist/δ-Antagonist and Dual μ-Agonist/δ-Agonist Opioid Ligands

Li, Tingyou; Shiotani, Kimitaka; Miyazaki, Akira; Tsuda, Yuko; Ambo, Akihiro; Sasaki, Yoshiyuki; Jinsmaa, Yunden; Marczak, Ewa D.; Bryant, Sharon D.; Lazarus, Lawrence H.; Okada, Yoshio

doi:10.1021/jm061238m

Cited by 39 publications

(30 citation statements)

References 70 publications

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“…The endomorphin-2 analog H-Dmt-Pro-Phe-NH-C 2 H 4 -Ph (Fujita et al, 2004) and the endomorphin-1 analog H-Dmt-Pro-Trp-D-1-Nal-NH 2 (Fichna et al, 2007) both showed high MOPr agonist potency and moderate DOPr antagonist activity in vitro. The endomorphin-2 analog H-Dmt-Pro-Tmp-Phe-NH 2 (Tmp is 29,49,69-trimethylphenylalanine) was reported to be a potent MOPr agonist/DOPr antagonist with high binding affinity for both receptors (Li et al, 2007).…”

Section: Mixed M-opioid Receptor Agonists/d-opioid Receptor Antagomentioning

confidence: 99%

Molecular Pharmacology ofδ-Opioid Receptors

et al. 2016

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Section: Mixed M-opioid Receptor Agonists/d-opioid Receptor Antagomentioning

confidence: 99%

Molecular Pharmacology ofδ-Opioid Receptors

et al. 2016

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“…And all these peptide derivatives exerted good m-bioactivities and abolished d-agonist activities, as shown in Table VI. 70 Consecutive substitution of Phe 3 with Nle (2-amino-capric acid), Cha (cyclohexylalanine), Lys, (F 5 )Phe (pentafluorophenylalanine), His (Fig. 7), as well as Ala, Val, Leu, Tyr rendered a series of new analogues with significantly decreased MOR affinity.…”

Section: A Pro: a Spacer Or An Unusual Visa For Mor Selectivitymentioning

confidence: 99%

“…61 Additionally, the EM-1 analogue 160 Dmt-Pro-Trp-Dmt-NH 2 was also found exhibiting potent m-agonist efficacy and moderate d-antagonist efficacy in vitro, the EM-2 analogues Dmt-Pro-Dmp-Phe-NH 2 161 and 162 Dmt-Pro-Tmp-Phe-NH 2 , containing Dmt in position 1 and Dmp or Tmp in position 3, were reported to demonstrate a potent mixed m-agonism/d-antagonism too (Table XVI), with high binding affinity for both receptors. 70 The MDAN (m-d agonist-antagonist) series of bivalent compounds, 170 containing linkers of different lengths (16-21 atoms), and pharmacophores derived from d-antagonist naltrindole (NTI) and m-agonist oxymorphone, were synthesized to examine the potential physical interactions between MOR and DOR in a putative MOR-DOR heterodimer. The obtained bivalent compounds exhibited potent agonist activities ranging from 1.6-to 45-fold higher than morphine in acute i.c.v.…”

Section: Design Of Endomorphin Analogues With Decreased Analgesic Tolmentioning

confidence: 99%

Endomorphins: potential roles and therapeutic indications in the development of opioid peptide analgesic drugs

Liu

Wang

2011

Medicinal Research Reviews

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The application of endomorphins as clinical available analgesic drugs has been impeded by their relatively poor receptor selectivity compared with alkaloid analgesics, rapid degradation in vivo, inefficient to penetrate the blood-brain barrier (BBB), and undesirable or toxic effects, such as acute tolerance and physical dependence, respiratory depression, and inhibition of gastrointestinal motility. Extensive studies have been performed so far striving to conquer these problems. In this article we review and discuss conformational and topographical modifications of the peptide amide bond and amino acid side groups to attain the most appropriate receptor binding affinity and high receptor selectivity; diverse strategies such as insertion of unnatural amino acids, covalent or noncovalent constraints as well as cyclization of linear peptides to enhance the enzymatic stability; designing of peptidomimetic ligands, glycopeptides, and N-terminal amidinationed analogues (such as incorporating guanidine into endomorphins) to penetrate the BBB. Also, several pertinent examples of bivalent and/or multivalent (such as mixed µ-agonist/δ-antagonist profile) compounds are discussed based on the existing literature and current data intending to give an insight into the development of opioid peptides expressing low tendency to produce acute tolerance and physical dependence.

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“…In the presence of strong bases the indole system reacts as an anion, mainly at the indole nitrogen, necessitating its protection. Considering these circumstances, it is easy to quite understand that the synthesis of EM-2 analogues in large quantity and diversity is preferable to those of EM-1 [13,75,76]; nonetheless, biologically active EM-1 analogues were patented [48,50–53]. …”

Section: Rational Design Of Endomorphin Analoguesmentioning

confidence: 99%

Engineering endomorphin drugs: state of the art

Lazarus

Okada

2012

Expert Opinion on Therapeutic Patents

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Importance of the field Although EM-1 (H-Tyr-Pro-Phe-Trp-NH2) and EM-2 (H-Tyr-Pro-Phe-Phe-NH2) are primarily considered agonists for the μ-opioid receptor (MOR), systematic alterations to specific residues provided antagonists and ligands with mixed μ/δ-opioid properties suitable for application to health related topics. Areas covered in this review This review attempts to succinctly provide insight on the development and bioactivity of endomorphin analogues during the past decade. Rational design approaches will focus on the engineering of endomorphin agonists, antagonists and mixed ligands for their application as a multi-target ligand. What the reader will gain While the application of endomorphins as antinociceptive agents and numerous biological endpoints were experimental delineated in laboratory animals and in vitro, clinical use is currently absent. However, structural alterations provide enhanced stability, formation of MOR antagonists or mixed and dual μ/δ-acting ligands could find considerable therapeutic potential. Take home message Aside from alleviating pain, EM analogues open new horizons in the treatment of medical syndromes involving neural reward mechanisms and extraneural regulation effects on homeostasis. Highly selective MOR antagonists may be promising to reduce inflammation, attenuate addiction to drugs and excess consumption of high caloric food, ameliorate alcoholism, affect the immune system and combat opioid bowel dysfunction.

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Bifunctional [2‘,6‘-Dimethyl-l-tyrosine]endomorphin-2 Analogues Substituted at Position 3 with Alkylated Phenylalanine Derivatives Yield Potent Mixed μ-Agonist/δ-Antagonist and Dual μ-Agonist/δ-Agonist Opioid Ligands

Abstract: Endomorphin-2 (H-Tyr-Pro-Phe-Phe-NH 2 ) and [Dmt 1 ]EM-2 (Dmt = 2',6'-dimethyl-

Cited by 39 publications

References 70 publications

Molecular Pharmacology ofδ-Opioid Receptors

Molecular Pharmacology ofδ-Opioid Receptors

Endomorphins: potential roles and therapeutic indications in the development of opioid peptide analgesic drugs

Engineering endomorphin drugs: state of the art

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