Reduction in opiate receptor reserve in morphine tolerant guinea pig ilea

Chavkin, Charles; Goldstein, Avram

doi:10.1016/0024-3205(82)90186-2

Cited by 50 publications

(20 citation statements)

References 7 publications

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“…Since the full agonist effect observed with parent peptide la in the MVD assay was also mediated by A receptors, it appears that the conformational constraints imposed in 2a through methylation of the D-Phe2 residue resulted in a reduced intrinsic activity at the A receptor. This decrease in the intrinsic activity is not observed in the GPI assay because of the very large reserve of ju receptors known to exist in this preparation (11). Further conformational restriction in the residue at position 2 through ring closure between the 2' position of the aromatic ring and the Na-methyl group in analogs 2a and 2b was achieved by synthesis of the corresponding D-and L-Tic2-tetrapeptide analogs (compounds 3a and 3b).…”

Section: Resultsmentioning

confidence: 99%

Differential stereochemical requirements of mu vs. delta opioid receptors for ligand binding and signal transduction: development of a class of potent and highly delta-selective peptide antagonists.

Schiller

Nguyen

Weltrowska

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

226

195

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Opioid peptide analogs consisting entirely of aromatic amino acid residues and contining conformationally restricted phenylalanine derivatives in position 2 of the peptide sequence were synthesized and pharmacologically characterized in vitro. Whereas the existence of at least three major opioid receptor classes (u, 6, and K) is now well-established, the development ofpotent opioid agonists and antagonists with high specificity for each receptor type and of ligands with receptor-specific agonist/antagonist properties continues to be an important goal in opioid pharmacology. The fact that A and 8 opioid receptors differ from one another in their conformational requirements for peptide ligands was first established through comparison of the receptor binding profiles of a cyclic enkephalin analog and its linear correlate (1). This observation led to the realization that conformational restriction of peptides either locally through incorporation of backbone or side-chain conformational constraints at a specific amino acid residue or more globally through peptide cyclizations may often result in improved receptor selectivity. The use of this strategy resulted in a number of conformationally restricted opioid peptide analogs with agonist properties that showed high preference for either 1L or 6 receptors (for a review, see ref.2). It has often been speculated but never demonstrated unambiguously that conformational restriction of peptides in some cases might also reduce or even totally abolish their intrinsic activity ("efficacy") and, thus, may produce partial agonists or antagonists. No examples of opioid peptide analogs with significant antagonist properties as a consequence of conformational restriction have been reported to date. The only opioid-peptide-derived antagonists with reasonable potency described so far were obtained through diallylation of the N-terminal amino group. An enkephalin analog of this type, NN-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174,864; Aib = aminoisobutyric acid) (3), has been useful as a 6-selective antagonist.In this paper we report that the tetrapeptide amide H-Tyr-D-Phe-Phe-Phe-NH2 (la) is a potent p-selective opioid agonist. This compound consists entirely of aromatic amino acids that can be conformationally restricted in a number of interesting ways. We show that substitution of the D and L isomers of the conformationally restricted phenylalanine analogs Na-methylphenylalanine (NMePhe) and tetrahydro-3-isoquinoline carboxylic acid (Tic) (Fig. 1) for D-Phe2 in peptide la produced astonishing changes in receptor affinities and intrinsic activities. Most importantly, these structureactivity studies defined a class of potent and selective 6 antagonists, characterized by the N-terminal sequence H-Tyr-Tic-Phe-. MATERIALS AND METHODSPeptide Synthesis. Peptide analogs 1-7 were synthesized by the usual solid-phase technique with N"-t-butyloxycarbonylprotected amino acids and with benzotriazol-1-yl-oxytris-(dimethylamino)phosphonium hexafluorophosphate as coupling agent as described el...

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Section: Resultsmentioning

confidence: 99%

Differential stereochemical requirements of mu vs. delta opioid receptors for ligand binding and signal transduction: development of a class of potent and highly delta-selective peptide antagonists.

Schiller

Nguyen

Weltrowska

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

226

195

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“…The molecular basis of tolerance manifests as a reduction in opioid agonist efficacy as demonstrated by a reduction in the rate of G-protein activation by the agonist-bound receptor complex (1)(2)(3). Furthermore, the modest reduction in cell surface receptor does not account for the observed decrease in agonist efficacy that accompanies tolerance measured biochemically (4,5), cytochemically (6), or electrophysiologically (7).…”

mentioning

confidence: 99%

“…Furthermore, the modest reduction in cell surface receptor does not account for the observed decrease in agonist efficacy that accompanies tolerance measured biochemically (4,5), cytochemically (6), or electrophysiologically (7). One mechanism of opioid receptor desensitization may be a receptor uncoupling from its effector system caused by receptor phosphorylation by a G-protein receptor kinase (GRK) 1 and subsequent binding of an arrestin.…”

mentioning

confidence: 99%

Threonine 180 Is Required for G-protein-coupled Receptor Kinase 3- and β-Arrestin 2-mediated Desensitization of the μ-Opioid Receptor in Xenopus Oocytes

Celver¹,

Lowe²,

Kovoor³

et al. 2001

Journal of Biological Chemistry

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, arr2(R169E), that desensitizes G protein-coupled receptors in an agonist-dependent but phosphorylation-independent manner. arr2(R169E) produced robust desensitization of MOR and MOR-(T180A) in the absence of GRK3 coexpression. These results demonstrate that the T180A mutation probably blocks GRK3-and arr3-mediated desensitization of MOR by preventing a critical agonist-dependent receptor phosphorylation and suggest a novel GRK3 site of regulation not yet described for other G-protein-coupled receptors.

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“…This follows from the classical work on spare receptors by Stephenson (4), Ariens et al (5), and Furchgott (9) showing that the greater the excess of functional receptors present, the lower the concentration of agonist required for effect. The second was the suggestion that tolerance to an opioid could be the consequence of a reduced opioid receptor reserve (10). In binding studies neither affinity nor site number in the guinea pig ileum myenteric plexus is affected by chronic morphine administration (11).…”

mentioning

confidence: 99%

Opioid receptor reserve in normal and morphine-tolerant guinea pig ileum myenteric plexus.

Chavkin¹,

Goldstein²

1984

Proc. Natl. Acad. Sci. U.S.A.

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We have measured the opioid receptor reserve in the guinea pig ileum myenteric plexus by means of the site-directed alkylating agent, 8-chlornaltrexamine. Treatment of the tissue with low (<10 nM) concentrations of /3-chlornaltrexamine caused a parallel shift of the log concentration-response curves for both normorphine and dynorphin A-(1-13). Analysis of the resulting curves indicated that the Kd values were 1.5 ± 0.5 x 10-6 and 10 ± 4 x 10-9, respectively.Using the naloxone Ke to distinguish between the ,u and K receptors in this tissue, we found that the receptor selectivities of normorphine and dynorphin A-(1-13) were unchanged after a maximum parallel shift, thus demonstrating that there are both spare IL and spare K receptors present. The spare-receptor fraction for both receptor types was about 90%. In morphine-tolerant preparations (chronic pellet implantation), there was an apparent reduction in the fraction of spare IL receptors without any change in the apparent affinity of normorphine. Reduction in the spare receptor fraction does not necessarily imply reduction in the number of binding sites. We suggest that this reduction in receptor reserve is the basis of opioid tolerance, since the agonist concentration needed to produce a given effect is expected to increase as the receptor reserve decreases.The irreversible opioid receptor antagonist, 3-chlornaltrexamine (f-CNA) is a site-directed alkylating agent synthesized and characterized by Portoghese and coworkers (1, 2). We showed previously (3) that in vitro treatment of the myenteric plexus-longitudinal muscle preparation from guinea pig ileum with low concentrations of 3-CNA results in a parallel shift to the right of the log concentration-response curves for [Leulenkephalin, normorphine, and dynorphin A-(1-13). Higher concentrations of f3CNA result in a reduced maximum response with concomitant decrease in slope. These findings provide classical evidence that there are spare opioid receptors (4, 5) in the myenteric plexus.With spare receptors present, the EC50 in the pharmacologic preparation should be lower than the Kd measured by radioreceptor binding techniques. Yet when Creese and Snyder (6) and later Cox et al. (7) [Leulenkephalin, which previously had acted on the 8 receptor, now exerted its full effect (with potency reduced by a factor of 100) through the As receptor, as indicated by a change in its naloxone sensitivity (see below). The first goal of the present study was therefore to determine what types of spare receptors are present in the guinea-pig myenteric plexus.Our initial demonstration of the presence of spare opioid receptors in an intact tissue preparation (3) had two important implications. The first was that the sensitivity of a neuron to an opioid could be controlled by the magnitude of the opioid receptor reserve. This follows from the classical work on spare receptors by Stephenson (4), Ariens et al. (5), and Furchgott (9) showing that the greater the excess of functional receptors present, the lower the concentra...

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Reduction in opiate receptor reserve in morphine tolerant guinea pig ilea

Cited by 50 publications

References 7 publications

Differential stereochemical requirements of mu vs. delta opioid receptors for ligand binding and signal transduction: development of a class of potent and highly delta-selective peptide antagonists.

Differential stereochemical requirements of mu vs. delta opioid receptors for ligand binding and signal transduction: development of a class of potent and highly delta-selective peptide antagonists.

Threonine 180 Is Required for G-protein-coupled Receptor Kinase 3- and β-Arrestin 2-mediated Desensitization of the μ-Opioid Receptor in Xenopus Oocytes

Opioid receptor reserve in normal and morphine-tolerant guinea pig ileum myenteric plexus.

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