Differentiation between opioid peptides by naltrexone

Rónai, András Z.; Berzétei, I.; Bajusz, S.

doi:10.1016/0014-2999(77)90281-3

Cited by 15 publications

(7 citation statements)

References 3 publications

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“…This concept is supported by the observations (Table 7) that enkephalin analogues which have an activity pattern more like that of morphine than that of natural enkephalin, require, in the mouse vas deferens, less naloxone for antagonism than the natural opioid peptides. Similar results have been *obtained by R6nai, Berzetei & Bajusz (1977) who showed that D-Met2-Pro5 amide was more readily antagonized by naltrexone than is methionine-enkephalin.…”

Section: Discussionsupporting

confidence: 87%

Effects of Changes in the Structure of Enkephalins and of Narcotic Analgesic Drugs on Their Interactions With Μ‐ and Δ‐receptors

Kosterlitz

Lord

Paterson

et al. 1980

British J Pharmacology

318

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The activity pattern of analogues of the enkephalins was determined in four parallel assays, the inhibition of the electrically evoked contraction of the guinea‐pig ileum and mouse vas deferens at 36°C and the inhibition of [3H]‐naltrexone and [3H]‐leucine‐enkephalin binding at 0 to 4°C in homogenates of guinea‐pig brain. The activity pattern was best characterized by the ratio of the potency in the guinea‐pig ileum to that in the mouse vas deferens (G.p.i./M.v.d.) and the ratio of the potency in inhibiting [3H]‐naltrexone binding to that in inhibiting [3H]‐leucine‐enkephalin binding (Nal/Leu). The enkephalins had low G.p.i./M.v.d. (0.02 to 0.09) and low Nal/Leu (0.05 to 0.18) ratios whereas the corresponding values for morphine were 7.0 and 7.5. Analogues obtained by substituting d‐Ala for Gly2and d‐Met or d‐Leu for l‐Met5or l‐Leu5showed only minor changes in G.p.i./M.v.d. (0.01 to 0.11) and in Nal/Leu (0.06 to 0.13) ratios. Analogues in which resistance to enzymatic degradation was brought about by amidation of the C‐terminal carboxylic group or methylation of the amino group of tyrosine or both modifications, had G.p.i./M.v.d. ratios of 1.2 to 5.5 and Nal/Leu ratios of 0.5 to 21. High values (2.1 and 3.4) were found for the potent antinociceptive analogue of Sandoz, Tyr‐d‐Ala‐Gly‐NCH3Phe‐Met(O)‐ol. In the mouse vas deferens, some of the analogues with high G.p.i./M.v.d. and Nal/Leu ratios were tested for antagonism by naloxone and found to require less than the high concentration needed for the natural enkephalins. C57/BL mice, which have a lowered sensitivity to morphine but a normal response to peptides with low G.p.i./M.v.d. and Nal/Leu ratios, had a lowered sensitivity to analogues with high ratios. In the alkaloid‐like series of narcotic analgesic drugs, ketobemidone, levorphanol, methadone, etorphine and the antagonist Mr 2266 had lower Nal/Leu ratios (1.0 to 2.8) than morphine, normorphine, naloxone and naltrexone (8 to 12). It would appear that compounds with low G.p.i./M.v.d. and Nal/Leu ratios interact mainly with δ‐receptors in the brain and peripheral nervous system while compounds with high ratios interact mainly with μ‐receptors. For antinociceptive action μ‐receptors may be more important than δ‐receptors.

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Section: Discussionsupporting

confidence: 87%

Effects of Changes in the Structure of Enkephalins and of Narcotic Analgesic Drugs on Their Interactions With Μ‐ and Δ‐receptors

Kosterlitz

Lord

Paterson

et al. 1980

British J Pharmacology

318

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“…In contrast, BA61 has a different N-terminal domain, which prefers the NOP receptor 67,[81][82][83] and yet a different C-terminal one (carboxyl group), which is perhaps responsible for DOP receptor preference. This observation is in good agreement with previous results, according to which the free carboxyl group containing enkephalins preferred DOP receptors 185,186 . Consequently, the observed pharmacological effect of this peptide might result on these changes.…”

Section: Discussionsupporting

confidence: 93%

Biochemical, functional and pharmacological characterization of novel bifunctional peptide ligands and nociceptin variants

Erdei

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Since the discovery of opioid heterodimers, more and more research groups have dealt with the development of a single ligand targeting multiple opioid receptors. It is widely accepted that multitarget ligands can constitute a much more effective solution for treating certain diseases than drug cocktails. The argument is that these ligands have a better therapeutic effect and can cause fewer side effects despite binding to more than one receptors, since the receptors constitute important therapeutic targets, and the interaction between separate drugs is eliminated 126. Potential strategies include targeting receptor dimers with bifunctional or bivalent ligands. Bifunctional and bivalent drugs are not clearly distinguished from each other in the literature, and are sometimes used as synonyms. According to Dietis et al., bifunctional ligands are designed to be non-selective compounds that comprise two protein-binding drug moieties (with or without a spacer) in one chemical structure and act at two different therapeutic targets (Fig. 2) 127. Bivalent ligands, on the other hand, are intended to be selective compounds, which composed of two distinct pharmacophores joined by a linker and usually have a larger molecular weight than bifunctional ligands (Fig. 2) 128. They are usually designed to bind to their two targets, which is not always achieved in practice 127. In the present thesis, the term bifunctional shall be used to refer to our newly synthesized ligands.

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“…ty r1 and phe4) which are substantial for opiate activity, we tested whether presence of the two benzene rings in an opioid structure (6) accounts for (a) the higher activity of an opioid compound in MVD than in GPI, and (b) the harder antagonizability of the bulk of opioid peptides by naloxone or naltrexone in MVD (17,23) as compared to normorphine.…”

Section: Discussionmentioning

confidence: 99%

“…Keeping in mind that MVD was the prepara tion, differentiating best between opioid pep tides (16,17,22,23), we made an attempt to characterize opiate receptors in MVD.…”

Section: Discussionmentioning

confidence: 99%

“…Some of them are potent anal gesics (2,3,25). One of the two in vitro assay systems used tire mouse vas deferens prepara tion was known to differentiate between non peptide and certain peptide narcotics, and also between the peptides themselves (16,17,22,23). Furthermore, comparison of activities of opioid peptides found in vitro (GP1 and MVD) offered the opportunity to predict analgesic activity of the peptide in question.…”

mentioning

confidence: 99%

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Kinetic Studies in Isolated Organs: Tools to Design Analgesic Peptides and to Analyze Their Receptor Effects

Rónai¹,

Berzétei²,

Székely³

et al. 1979

Pharmacology

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The opioid activities of peptide and non-peptide narcotics were studied in longitudinal muscle strip of guinea pig ileum (GPI) and in mouse vas deferens (MVD). The comparison of agonist activities of peptides found in GPI and MVD offered the opportunity to predict the presence but not the magnitude of potential analgesic activity. The kinetics of the antagonism between naltrexone and different types of agonists were also determined in these systems. Using C-6 epimers of naltrexone, it was found that the site of opiate receptors recognizing the information provided by the C-6 substituent of naltrexone are different in GPI and MVD.

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Differentiation between opioid peptides by naltrexone

Cited by 15 publications

References 3 publications

Effects of Changes in the Structure of Enkephalins and of Narcotic Analgesic Drugs on Their Interactions With Μ‐ and Δ‐receptors

Effects of Changes in the Structure of Enkephalins and of Narcotic Analgesic Drugs on Their Interactions With Μ‐ and Δ‐receptors

Biochemical, functional and pharmacological characterization of novel bifunctional peptide ligands and nociceptin variants

Kinetic Studies in Isolated Organs: Tools to Design Analgesic Peptides and to Analyze Their Receptor Effects

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