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

  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},
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.
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
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
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.
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.
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.


Some thoughts on the significance of enkephalin, the endogenous ligand.
Interactions between endogenous enkephalin and exogenous opiate at the opiate receptor are discussed as a possible basis of tolerance and dependence caused by chronic administration of opiates.
Purification and properties of enkephalin - the possible endogenous ligand for the morphine receptor.
It is suggested that the peptide extracted from the pig brain may have a wide neurophysiological role in the brain and possibly in other tissues.
Studies on the primary structure of human β‐lipotropic hormone
The isolation and some characteristics of a lipolytic peptide from human pituitaries were described and structural studies to the human P-LPH were extended.
Search for an endogenous ligand for the opiate receptor.
The factor inhibited binding to the opiate receptor in synaptic plasma membranes of rat brain and to the receptor of the guinea-pig ileum although it was less effective on the latter, particularly after long-term incubation.
An endogenous morphine-like factor in mammalian brain.
Abstract An endogenous morphine-like substance (MLF) found in rat and calf brains has a regional distribution correlating with that of opiate receptors, with the highest levels in the caudate and
Isolation and Amino-acid Sequence of β-LPH from Sheep Pituitary Glands
SEVERAL adenohypophyseal hormones have been demonstrated to possess in vitro lipotropic activity; these include growth, adrenocorticotropic, thyrotropic, α-melanocyte-stimulating and
Purification and properties
It is an opioid agonist on the guinea pig myenteric plexus-longitudinal muscle preparation, and on the mouse vas deferens, and it binds to opiate receptors in homogenates of Guinea pig brain.
Isolation of an endogenous compound from the brain with pharmacological properties similar to morphine
  • J. Hughes
  • Chemistry, Medicine
    Brain Research
  • 1975
It is suggested that the compound isolated in this investigation forms part of a central pain suppressive system and may also have a wider neurochemical role in the brain.
A mass-spectrometric sequence study of the enzyme ribitol dehydrogenase from Klebsiella aerogenes.
The first detailed results of the application of a low-resolution mixture analysis approach to the sequence analysis of an enzyme, ribitol dehydrogenase, are given and the overall sequencing strategy evolved is assessed.
Studies towards the complete sequence determination of proteins by mass spectrometry; a rapid procedure for the successful permethylation of histidine containing peptides
A strategy is described which offers the distinct advantage of rapid sequence assignment, preempting the necessity for purification and isolation of individual peptides, and some experiments are described which have this advantage.