Enkephalins analgesic activity

Several enzymes, none of which are completely specific for the enkephalins, are known to cleave Leu- and Met-enkephalin at various peptide bonds. The main enzymes that degrade enkephalin are 2inc metaHopeptidases. The first enkephalin-degrading enzyme to be identified, an aminopeptidase which cleaves the amino terminal Tyr-Gly bond (179), has been shown to be aminopeptidase-N (APN) (180). It is a cytoplasmic enzyme which is uniformly distributed throughout the brain. The increased analgesic activity of synthetic enkephalins substituted by D-amino acids at position 2, eg,... 

The identification of the morphine receptor spurred an effort in many laboratories to find an endogenous agonist for which that receptor was normally intended. Ultimately, a pair of pentapeptides that bound quite tightly to opiate receptors were isolated from mammalian brains. These peptides, called enkephalins (2, 3), show many of the activities of synthetic opiates in isolated organ systems. They do in fact show analgesic activity when injected directly into the brain. It is thought that lack of activity by other routes of administration is due to their rapid inactivation by peptide cleaving enzymes. 

Figure 5.32 Analgesic activity of the fluoro-enkephalins on the mouse. ...

Pless, J., Bauer, W., Cardinaux, F., Closse, A., Hauser, D., Hugenin, R., Roemer, D., Buescher, H.-H., Hill, R.C. Synthesis, opiate receptor binding and analgesic activity of enkephalin analogues, Helv. Chim. Acta 1979, 62, 398-411. 

Roemer D., Buescher H. H., Hill R. C., Pless J., Bauer W., Cardinaux F., Closse A., Hauser D., Huguenin R., A synthetic enkephalin analogue with prolonged parenteral and oral analgesic activity, Nature 1977, 268, 547-549... 

Over 1000 enkephalin derivatives have now been synthesized, and in some of them it has been possible to increase the analgesic effect with respect to enkephalin 33 37). The enkephalin derivative 18 38) (Sandoz, FK 33-824), in which enzymatic degradation is blocked, has proved to be strongly analgesically active in animals. 

The analgesically active dipeptide kyotorphin Tyr-Arg55), which supposedly causes secretion of Met-enkephalin, was isolated from bovine hypothalamus in 1979 by Takagi et al., as was the pentapeptide neo-kyotorphin (NIC) Thr-Ser-Lys-Tyr-Arg 56) in 1982. 

The prospects of making pharmacologically more active compounds as well as substances that do not cause dependence by modifying enkephalins, spur the peptide chemist on to greater efforts. As always, the fact that analgesically active peptides are rapidly degraded by enzymes after intracerebroventricular administration in animals represents the main barrier to their therapeutic application. 

LY 127623 BCW59-A) is a synthetic pentapeptide analogue of enkephalin, and is an opioid RECEPTOR agonist with OPIOID analgesic activity. 

Syncurine decamethonium iodide, syndyphalin (Syndyphalin 33) is a synthetic pseudopeptide enkephalin analogue, and is an OPIOID RECEPTOR AGONIST with OPIOID ANALGESIC activity, syndyphalin 25 (SD 25) is a synthetic pseudopeptide enkephalin analogue, and is a (p) opioid RECEPTOR AGONIST with OPIOID ANALGESIC activity. 

The penetration of the blood-brain barrier (BBB) by enkephalin analogs is relatively low and therefore their analgesic activity after sys-... 

All 15 compounds are found to have either the Met- or the Leu-enkephalin skeleton at their N-terminus, which emphasizes the importance of this pentapeptide structure towards analgesic activity. It has also been shown conclusively that the tyrosine part of these molecules is essential to activity and much has been made of the fact that there is a tyrosine skeleton in the morphine skeleton (Fig. 12.39). 

Evaluation of the analgesic activity of morphine, enkephalins and their synthetic analogs... 

A synthetic enkephalin analog with prolonged parenteral and oral analgesic activity Roemer, Dietmar Buescher, Heinz H. Hill, Ronald C. Pless, Janos ... 

Enkephalins. Term derived from the Greek enk6phalo =brain for certain oligopeptides with analgesic activity (brain peptides, neuropeptides) which were discovered in human brain tissue in 1975. Distinctions are drawn between Met -and Leu -E. H-Tyr-Gly-Gly-Phe-X-OH X = Met or Leu... 

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