Identification of two related pentapeptides from the brain with potent opiate agonist activity

@article{Hughes1975IdentificationOT,
  title={Identification of two related pentapeptides from the brain with potent opiate agonist activity},
  author={John Hughes and T. W. Smith and Hans W. Kosterlitz and Linda A. Fothergill and Barry A. Morgan and Howard R. Morris},
  journal={Nature},
  year={1975},
  volume={258},
  pages={577-579}
}
Enkephalin, a natural ligand for opiate receptors is composed of the pentapeptides H–Tyr–Gly–Gly–Phe–Met–OH and H–Tyr–Gly–Gly–Phe–Leu–OH. The evidence is based on the determination of the amino acid sequence of natural enkephalin by the dansyl–Edman procedure and by mass spectrometry followed by synthesis and comparison of the natural and synthetic peptides. 
Opiate receptor affinities and behavioral effects of enkephalin: structure-activity relationship of ten synthetic peptide analogues.
Abstract Synthetic met- and leu-enkephalin bind to rat brain opiate receptors with 1 2 and 1 7 the affinity of morphine. The aromatic hydroxyl moiety of the tyrosine residue is critical for receptor
Opiate receptor affinity of peptides related to Leu-enkephalin.
Abstract Several analogs of Leu-enkephalin were synthesized by the standard solid phase procedure in order to investigate structural requirements for binding to opiate receptors. Decisive features
Potent tetrapeptide enkephalins.
TLDR
It is shown that the potency losses resulting from the removal of glycine 3 can be fully attenuated by substitution of D-alanine in position two and derivatization of the acid to the amide.
Evidence for analgesic activity of enkephalin in the mouse
TLDR
It is indicated that the two natural compounds induce analgesia in mice, whereas the two analogues are devoid of such activity.
Morphine-like peptides in mammalian brain: isolation, structure elucidation, and interactions with the opiate receptor.
  • R. Simantov, S. Snyder
  • Chemistry, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1976
TLDR
Sodium and manganese effects on opiate receptor interactions show that both peptides are agonists, whereas leucine enkephalin may be a "purer" agonist than methionine enkphalin.
Opioid activity of synthetic and naturally occurring enkephalin peptides.
TLDR
Injection of peptides intracerebrally indicated that an analog with the addition of a D-alanine at the C-terminus produced potent analgesia and had a longer duration of action than methionine-enkephalin, suggesting that peptidase hydrolysis at the N -terminus may not be the only important mechanism of inactivation.
Enkephalin analogs modified in the aromatic ring of the N-terminal tyrosine residue
Abstract Two analogs of Leu 5 -enkephalin, (1- O -methyltyrosine,5-leucine)-enkephalin and [1-(3′-amino)-tyrosine,5-leucine]-enkephalin, were synthesized by classical methods. Both analogs show high
Analogues of both Leu- and Met-enkephalin containing a constrained dipeptide isostere prepared from a Baylis-Hillman adduct
An efficient route was developed for the synthesis of the Fmoc-protected dipeptide 4, isostere of Gly-Gly containing an α-methylene β-amino acid; the conformationally restricted analogues of
Circulating Opioids in Man
Currently, all known mammalian endogenous opioid peptides belong to one of three peptide families, each derived from a distinct precursor molecule: pro-enkephalin (PENK), pro-opiomelanocortin (POMC)
Synthesis and biological activities of position one and three transposed analogs of the opioid peptide YKFA.
TLDR
Transposing Phe and Tyr, a modification found to promote mu antagonist activity in opioid/somatostatin hybrids, gave surprisingly high mu agonist activities for several related analogs, considering the lack of a 1-position hydroxyl function.
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TLDR
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