Synthesis and opioid activities of stereoisomers and other D-amino acid analogs of methionine-enkephalin

Coy, David H.; Kastin, Abba J.; Schally, Andrew V.; Morin, O.; Caron, Nicolas; Labrie, Fernand; Walker, J. Michael; Fertel, Richard H.; Berntson, Gary G.; Sandman, CA

doi:10.1016/0006-291x(76)90857-3

Cited by 133 publications

(35 citation statements)

References 19 publications

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“…)/kg per hr or octapeptide of cholecystokinin (OP-CCK) at a dose of 0-25 jug/kg per hr was administered intravenously to induce pancreatic secretion of bicarbonate and protein similar to that observed in the experiments with feeding or duodenal acidification. Following an initial 90 min period when pancreatic secretion stimulated by food and duodenal acidification or exogenous hormones produced a steady state, Met-enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH) synthesized by a solid phase method (Coy, Kastin & Schally, 1976), was infused at a dose of 40 /ctg/kg per hr for another 60 min. Finally, the secretary stimulant alone was continued for an additional 60 min period.…”

Section: Methodsmentioning

confidence: 99%

Enkephalin inhibits the release and action of secretin on pancreatic secretion in the dog.

Chey¹,

Coy²,

Konturek³

et al. 1980

The Journal of Physiology

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SUMMARY1. Pancreatic bicarbonate and protein secretion as well as immuno-reactive plasma secretin concentration in response to a meal, duodenal acidification and exogenous secretin or octapeptide of cholecystokinin (OP-CCK) have been measured following administration of methionine-enkephalin in chronic pancreatic fistula dogs.2. Methionine-enkephalin inhibited pancreatic responses to both exogenous hormones (secretin and OP-CCK) and to endogenous hormones released from the gut by food or duodenal acidification.3. Naloxone, a potent opiate receptor antagonist, partly prevents this methionineenkephalin-induced inhibition of pancreatic secretion suggesting that this effect might be mediated by opiate receptors.4. The inhibitory effect of methionine-enkephalin on pancreatic response to endogenous stimulants was more pronounced than that to exogenous hormones and was accompanied by a significant reduction in plasma immuno-reactive secretin concentration.5. This study indicates that methionine-enkephalin inhibits pancreatic secretion, at least in part, by suppressing the release of the intestinal hormones stimulating the exocrine pancreas.

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Section: Methodsmentioning

confidence: 99%

Enkephalin inhibits the release and action of secretin on pancreatic secretion in the dog.

Chey¹,

Coy²,

Konturek³

et al. 1980

The Journal of Physiology

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“…D-Ala* -enkephalinamide [28,29] is a potent long lasting analgesic with a high affinity for the opiate receptor whereas the L-Ala analog exhibits only weak receptor binding. These results suggest that the conformations permissible for the D-Ala and Aib residues fit the opiate receptor whereas the conformations adopted by the L-Ala residue are unfavourable for receptor interactions.…”

Section: Resultsmentioning

confidence: 99%

A stereochemically‐constrained enkephalin analog

Nagaraj

Balaram

1978

FEBS Letters

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“…Therefore, the presence of methionine sulfoxide was established by the amino acid analysis of the peptide sample after digestion with carboxypeptidase Y. To confirm the structure of this hexapeptide, it was synthesized by solid-phase methods (11), and the purified peptide was then oxidized with H202 to convert methionine to its sulfoxide (13). The RFS of oxidized natural and synthetic peptides were then compared by TLC on silica gel in two solvent systems as shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Isolation and structure of pro-methionine-enkephalin: Potential enkephalin precursor from porcine hypothalamus

Huang¹,

Chang²,

Kastin³

et al. 1979

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

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A hexapeptide that we have named pro-methionine-enkephalin has been isolated from acid extracts of porcine hypothalami and found to have the amino acid sequence H-Tyr-Gly-Gly-Phe-Met(O)Arg-OH. This peptide is not a fragment of either porcine -1lipotropin or -endorphin, which suggests that it could be a precursor of [Metienkephalin in the brain by a pathway differing from the one usually postulated.The existence of still larger precursors of [Metlenkephalin, perhaps related to the recently reported a-neo-endorphin, is strongly implied by these studies. Synthetic H-Tyr-Gly-GlyPhe-Met-Arg-OH exhibited low, but significant, opiate activity in vitro.The isolation from mammalian brain of the two pentapeptides,[Met]-and [Leu]enkephalin, with morphipomimetic (opioid) (1) activity has stimulated a large number of biochemical, neurophysiological and neuropharmacological studies. The endorphins (a, A3, and hy) structurally related to [Metlenkephalin and f-lipotropin (fl-LPH),y have also been isolated and characterized as endogenous ligands of opiate receptors (2-6). Recently, a-neo-endorphin, a form of "big" [Leujenkephalin, was isolated from porcine hypothalami and proposed to be a precursor of the pentapeptide (7).In the course of fractionation of porcine hypothalamic extracts in search for corticotropin-releasing factor (CRF), we have isolated and structurally characterized an opioid hexapeptide whose first five residues are the same as in [Metlenkephalin. However, the sixth residue differs from that present in the known endorphins, and the entire sequence is not common to that of f3-LPH, which is considered to be a precursor of the endorphins and [Metjenkephalin (2).MATERIALS AND METHODS Purification. The extract obtained from 470,000 pig hypothalami was the same as that used for the isolation of porcine somatostatin (8). All the extraction and purification procedures and most methods used for homogeneity, 'composition, and sequence studies have been described in detail (8, 9).High-Pressure Liquid Chromatography (HPLC). The apparatus used for HPLC consisted of a Waters Associates model 204 liquid chromatograph equipped with a UK6 injector, two 6000A pumps, a 660 programmer, and Schoeffel vuriablewavelength detector. Reverse-phase HPLC was performed on Au-Bondapak C18 columns (0.4 X 30 cm) by gradient elution.The buffer consisted of 0.01 M ammonium acetate adjusted to pH 4.0 with acetic acid and redistilled 2-propanol as the organic eluent.Homogeneity Tests. Thin-layer chromatography (TLC) was carried out on cellulose or silica gel plates. Two solvent systems were used: (i) 1-butanol/acetic acid/water/ethyl acetate (1: 1:1:1, vol/vol) and (ii) 1-butanol/pyridine/acetic acid/water (15:10:3:12, vol/vol). The developed chromatograms were visualized by spraying with ninhydrin/cadmium reagent.Amino Acid Analysis. Peptides (1-3y g) were hydrolyzedfor 24 hr at 1100C with 4 M methanesulfonic acid/0.2% tryptamine. The analyses were performed on a' Beckman 119 CL amino acid analyzer.Edman-Dansyl Procedure. The manual E...

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Synthesis and opioid activities of stereoisomers and other D-amino acid analogs of methionine-enkephalin

Cited by 133 publications

References 19 publications

Enkephalin inhibits the release and action of secretin on pancreatic secretion in the dog.

Enkephalin inhibits the release and action of secretin on pancreatic secretion in the dog.

A stereochemically‐constrained enkephalin analog

Isolation and structure of pro-methionine-enkephalin: Potential enkephalin precursor from porcine hypothalamus

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