Receptor constants for endomorphin-1 and endomorphin-1-ol indicate differences in efficacy and receptor occupancy

Al-Khrasani, M.; Orosz, György; Kocsis, László; Farkas, Viktor; Magyar, Anna; Lengyel, Imre; Benyhe, Sándor; Borsodi, Anna; Rónai, András Z.

doi:10.1016/s0014-2999(01)01014-7

Cited by 36 publications

(28 citation statements)

References 24 publications

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“…These results suggest that the test compound has less pronounced gastrointestinal side effects, though we did not expect it, since it showed high efficacy in in vitro assays, implying that it behaves as a full agonist. It is noteworthy that similar promising favorable profile had also been reported by Holtman and coworkers for morphine-6-Osulfate (Holtman et al, 2010), but in its case the partial agonistic property might explain the mild gastrointestinal inhibitory action (Lackó et al, 2012;Al-Khrasani et al, 2001). Morphine, on the other hand, is also a partial agonist, but induced more pronounced antitransit effect than the other two derivatives.…”

Section: Tablesupporting

confidence: 64%

“…Our findings indicate that 14-O-methylmorphine similar to DAMGO but not to morphine produced high efficacy. The full and partial agonist character of an opioid agonist is an important issue, since many reports described that a decrease in antinociceptive efficacy of currently used opioid is a consequence of decrease in opioid receptor reserve (Al-Khrasani et al, 2001, 2007Khalefa et al, 2013;Riba et al, 2010). Therefore, only opioid of high efficacy (having spare receptors) will be able to produce antinociception by chronic administration without substantial loss of effect.…”

Section: Tablementioning

confidence: 99%

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14-O-Methylmorphine: A Novel Selective Mu-Opioid Receptor Agonist with High Efficacy and Affinity

Zádor

Balogh

Váradi

et al. 2017

European Journal of Pharmacology

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A B S T R A C T14-O-methyl (14-O-Me) group in morphine-6-O-sulfate (M6SU) or oxymorphone has been reported to be essential for enhanced affinity, potency and antinociceptive effect of these opioids. Herein we report on the pharmacological properties (potency, affinity and efficacy) of the new compound, 14-O-methylmorphine (14-OMeM) in in vitro. Additionally, we also investigated the antinociceptive effect of the novel compound, as well as its inhibitory action on gastrointestinal transit in in vivo. binding. In addition, 14-O-MeM compared to morphine showed higher affinity for μ-opioid receptor (MOR). In vivo, in rat tail-flick test 14-O-MeM proved to be stronger antinociceptive agent than morphine after peripheral or central administration. Additionally, both compounds inhibited the gastrointestinal peristalsis. However, when the antinociceptive and antitransit doses for each test compound are compared, 14-O-MeM proved to have slightly more favorable pharmacological profile. Our results affirm that 14-O-MeM, an opioid of high efficacy and affinity for MOR can be considered as a novel analgesic agent of potential clinical value.

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Section: Tablesupporting

confidence: 64%

Section: Tablementioning

confidence: 99%

14-O-Methylmorphine: A Novel Selective Mu-Opioid Receptor Agonist with High Efficacy and Affinity

Zádor

Balogh

Váradi

et al. 2017

European Journal of Pharmacology

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“…The endomorphins were reported to be partial agonists at MOPr in some cases, such as in GTP␥S binding assays with spinal cord and thalamus (Hosohata et al, 1998;Narita et al, 1998;Sim et al, 1998;Xie et al, 2008) and in inhibition of neuronal Ca 2ϩ currents (Connor et al, 1999), whereas the endomorphins behaved as full agonists in other cases, such as inhibition of contraction of mouse vas deferens (Al-Khrasani et al, 2001;Rónai et al, 2006); such differences are likely to depend in part on the receptor reserve in each tissue. In the present study with LC neurons, we found endomorphin-2 to be a full agonist for activation of GIRK current.…”

Section: Discussionmentioning

confidence: 99%

Endomorphin-2: A Biased Agonist at the μ-Opioid Receptor

Rivero¹,

Llorente²,

McPherson³

et al. 2012

Mol Pharmacol

101

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Previously we correlated the efficacy for G protein activation with that for arrestin recruitment for a number of agonists at the -opioid receptor (MOPr) stably expressed in HEK293 cells. We suggested that the endomorphins (endomorphin-1 and -2) might be biased toward arrestin recruitment. In the present study, we investigated this phenomenon in more detail for endomorphin-2, using endogenous MOPr in rat brain as well as MOPr stably expressed in HEK293 cells. For MOPr in neurons in brainstem locus ceruleus slices, the peptide agonists [DAla 2 ,N-Me-Phe 4 ,Gly 5 -ol]-enkephalin (DAMGO) and endomorphin-2 activated inwardly rectifying K ϩ current in a concentrationdependent manner. Analysis of these responses with the operational model of pharmacological agonism confirmed that endomorphin-2 had a much lower operational efficacy for G protein-mediated responses than did DAMGO at native MOPr in mature neurons. However, endomorphin-2 induced faster desensitization of the K ϩ current than did DAMGO. In addition, in HEK293 cells stably expressing MOPr, the ability of endomorphin-2 to induce phosphorylation of Ser375 in the COOH terminus of the receptor, to induce association of arrestin with the receptor, and to induce cell surface loss of receptors was much more efficient than would be predicted from its efficacy for G protein-mediated signaling. Together, these results indicate that endomorphin-2 is an arrestin-biased agonist at MOPr and the reason for this is likely to be the ability of endomorphin-2 to induce greater phosphorylation of MOPr than would be expected from its ability to activate MOPr and to induce activation of G proteins.

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“…[33] In fact, the C-terminal residue is essential for high-affinity binding of EMs to the MOR. [23][24][25][26] Many results have suggested that the bioactivity of this sequence (Tyr-Pro-Trp/Phe-X-NH 2 ) is determined by the nature of the fourth residue, [24] and the third aromatic pharmacophore is crucial for bioactivity. [20,24] For example, in Tyr-W-MIF-1 (Tyr-ProTrp-Gly-NH 2 ), the affinity increases about 200-fold [20] if Gly 4 is substituted by the hydrophobic residue Phe, resulting in an observation that actually led to the discovery of EMs.…”

Section: Solution Conformation Analysismentioning

confidence: 99%

“…[23] The C-terminal address fragment Phe 4 -NH 2 plays an important role in ligand recognition. [23][24][25][26] The replacement of Phe 4 by bPhe, [27] l/d-Dmp, [28] aromatic, heteroaromatic, or aliphatic groups [29] considerably decreased affinity and selectivity toward the receptor; however, incorporation of (2S,3S)-bMePhe 4 resulted in analogues with m-opioid affinities fourfold higher than the parent peptides. [17] To get insight into the important role of the third aromatic ring arrangement, we report herein the modification of the C termini of EM analogues ([Xaa 4 -R]EMs) by substitution of the Phe 4 group with nonaromatic residues and by termination with benzyl groups.…”

Section: Introductionmentioning

confidence: 99%

Structure–Activity Study on the Spatial Arrangement of the Third Aromatic Ring of Endomorphins 1 and 2 Using an Atypical Constrained C Terminus

Shao

Cui

et al. 2007

ChemMedChem

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The discovery of endomorphins (EMs) has opened the possibility of searching for new analgesics. However, the design of peptide analgesics has proven to be very difficult as a result of their conformational flexibility and a lack of clarity in structure-activity relationships (SAR). In EMs, the amino acid side chains exhibit considerable conformational flexibility, especially in the third aromatic ring, which is free to adopt a bioactive conformation. To resolve these problems, a series of C terminus EM analogues, [Xaa(4)-R]EMs, modified through the substitution of Phe(4) with nonaromatic residues and termination with benzyl groups, were designed to generate conformational constrains of the third aromatic ring by amide bond and torsion angles (phi(4) and psi(4)) of Xaa(4). Introduction of (S)-alpha-methyl or (S)/(R)-alpha-carboxamide on the methylene unit of the benzyl group was designed to produce an atypical topographical constraint (phi(5)) of the third aromatic ring rotation. Interestingly, some EM derivatives, with elimination of the C-terminal carboxamide group and significant changes in the address sequence (Phe(4)-NH(2)), still exhibited higher mu-opioid receptor (MOR) affinity than unmodified EMs. In contrast, some analogues with incorrectly constrained C termini displayed very low affinity and pharmacological activities. Thus, our results indicate that these EM analogues, with atypical constrained C termini, provide model compounds with potent MOR agonism. They also give evidence that the proper spatial orientation and conformational restriction of the third aromatic ring are crucial for the interaction of EMs with MOR.

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Receptor constants for endomorphin-1 and endomorphin-1-ol indicate differences in efficacy and receptor occupancy

Cited by 36 publications

References 24 publications

14-O-Methylmorphine: A Novel Selective Mu-Opioid Receptor Agonist with High Efficacy and Affinity

14-O-Methylmorphine: A Novel Selective Mu-Opioid Receptor Agonist with High Efficacy and Affinity

Endomorphin-2: A Biased Agonist at the μ-Opioid Receptor

Structure–Activity Study on the Spatial Arrangement of the Third Aromatic Ring of Endomorphins 1 and 2 Using an Atypical Constrained C Terminus

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