Structural studies of [2′,6′-dimethyl-l-tyrosine1]endomorphin-2 analogues: enhanced activity and cis orientation of the Dmt-Pro amide bond

Okada, Yoshio; Fujita, Yoshio; Motoyama, T.; Tsuda, Yuko; Yokoi, Toshio; Li, Tingyou; Sasaki, Yoshiyuki; Ambo, Akihiro; Jinsmaa, Yunden; Bryant, Sharon D.; Lazarus, Lawrence H.

doi:10.1016/s0968-0896(03)00068-3

Cited by 54 publications

(45 citation statements)

References 31 publications

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“…The replacement of the Tyr residue in this peptide with Dmt residue yielded a compound (Dmt-Pro-Phe-NH 2 ) endowed with high agonist activity at both (IC 50 in GPI = 0.07 nM) and ␦ (IC 50 in MVD = 1.87 nM) sites owing to simultaneous increase in agonist potency at both the receptors. 29 Some of the C-terminal arylamide analogs such as Dmt-Pro-Phe-NH-1-naphthyl also displayed mixed / ␦ agonist activities. 30 Another Dmt containing peptide that has recently been shown to possess mixed / ␦ agonist activity is the tetrapeptide H-Dmt-D-Arg(NO 2 )-Phe-Lys-(Z)-NH 2 .…”

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confidence: 99%

Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

Ananthan

2006

AAPS J

123

103

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A BSTRACTOpioids are widely used in the treatment of severe pain. The clinical use of the opioids is limited by serious side effects such as respiratory depression, constipation, development of tolerance, and physical dependence and addiction liabilities. Most of the currently available opioid analgesics exert their analgesic and adverse effects primarily through the opioid receptors. A large number of biochemical and pharmacological studies and studies using genetically modifi ed animals have provided convincing evidence regarding the existence of modulatory interactions between opioid and ␦ receptors. Several studies indicate that ␦ receptor agonists as well as ␦ receptor antagonists can provide benefi cial modulation to the pharmacological effects of agonists. For example, ␦ agonists can enhance the analgesic potency and effi cacy of agonists, and ␦ antagonists can prevent or diminish the development of tolerance and physical dependence by agonists. On the basis of these observations, the development of new opioid ligands possessing mixed agonist/ ␦ agonist profi le and mixed agonist/ ␦ antagonist profi le has emerged as a promising new approach to analgesic drug development. A brief overview of -␦ interactions and recent developments in identifi cation of ligands possessing mixed agonist/ ␦ agonist and agonist/ ␦ antagonist activities is provided in this report. K EYWORDS:Analgesics , Opioid Ligands , Mixed Mu/Delta agonists , Mixed Mu agonist/Delta antagonists , Peptides , Nonpeptides INTRODUCTIONOpioid analgesics are the standard therapeutic agents for the treatment of moderate-to-severe pain. These drugs exert their analgesic activity through their interaction with the opioid , ␦ , or receptors as agonists. The clinical usefulness of opioid agonists such as morphine, however, is limited by signifi cant side effects such as respiratory depression, constipation, development of tolerance and physical dependence, and addiction potential. One approach to limit -receptor-mediated side effects is to selectively target ␦ and opioid receptors. This approach has been explored using agonist ligands selective for ␦ and opioid receptors but has seen only limited success. The ␦ agonists generally display limited analgesic effi cacy and receptor agonists are limited to their use as peripheral analgesics owing to their psychotomimetic and dysphoric central effects. An alternative approach that is gaining considerable interest is the development of compounds that possess mixed opioid activity at the different opioid receptors. 1 , 2 Several lines of evidence indicate the existence of physical and functional interactions between the opioid receptors, particularly between the and ␦ receptors. Several biochemical and pharmacological studies using and ␦ receptor ligands gave an early indication of such interactions between the and ␦ receptors. [3][4][5][6] The and ␦ opioid receptors exist on overlapping populations of neurons in painmodulating regions of the central nervous system, and the presence of both and ␦ receptors ...

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confidence: 99%

Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

Ananthan

2006

AAPS J

123

103

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“…In contrast to EM2, the NMR measurements showed the predominance of cisisomers for its analogs, in which Tyr 1 amino acid was substituted by 2',6'-dimethyltyrosine (Dmt), 2',3',6'-trimethyltyrosine (Tmt), 2'-ethyl-6'-methyltyrosine (Emt), 2',6'-diethyltyrosine (Det), 2'-isopropyl-6'-methyltyrosine (Imt), and 2',6'-diisopropyltyrosine (Dit) residues, respectively [31] [32]. However, similarly to EM2, a cis/trans ratio of ca.…”

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confidence: 99%

Structural Investigation of Endomorphins by Experimental and Theoretical Methods: Hunting for the Bioactive Conformation

Leitgeb

2007

Chemistry & Biodiversity

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“…al., which showed that incorporating Dmt into endomorphin 1 and 2 significantly increases μ-opioid receptor affinity and analgesic activity assays in vivo. 35,39,60 It is clear that the presence of a C8Laa residue on the N-terminus had little effect on the tight binding of the Dmt-peptide.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides

Koda

Borgo

Wessling

et al. 2008

Bioorganic & Medicinal Chemistry

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Endomorphin 1 (Endo-1 = Tyr-Pro-Trp-Phe-NH 2 ), an endogenous opioid with high affinity and selectivity for μ-opioid receptors, mediates acute and neuropathic pain in rodents. To overcome metabolic instability and poor membrane permeability, the N-and C-termini of Endo-1 were modified by lipoamino acids (Laa) and/or sugars, and 2′,6′-dimethyltyrosine (Dmt) replacement of Tyr. Analogues were assessed for μ-opioid receptor affinity, inhibition of cAMP accumulation, enzymatic stability, and permeability across Caco-2 cell monolayers. C-terminus modification decreased receptor affinity, while N-terminus C8-Laa improved stability and permeability with slight change in receptor affinity. Dmt provided a promising lead compound: [C8Laa-Dmt 1 ]-Endo-1 is 9 times more stable (t ½ = 43.5 min), > 8-fold more permeable in Caco-2 cell monolayers, and exhibits 140-fold greater μ-opioid receptor affinity (K iμ = 0.08 nM).

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Structural studies of [2′,6′-dimethyl-l-tyrosine1]endomorphin-2 analogues: enhanced activity and cis orientation of the Dmt-Pro amide bond

Cited by 54 publications

References 31 publications

Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

Structural Investigation of Endomorphins by Experimental and Theoretical Methods: Hunting for the Bioactive Conformation

Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides

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