ENKEPHALINS

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ENKEPHALINS

• THE BODYS PAINKILLERS

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Met-Enkephalin H-Tyr-Gly-Gly-Phe-Met-OH
Leu-Enkephalin H-Tyr-Gly-Gly-Phe-Leu-OH
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NOTES - ENKEPHALINS Endogenous peptides acting
as neurotransmitters in brain Enkephalin - Greek
for in the head Bind to delta receptor
(d) Approximately 15 other endogenous peptides
of 5-26 AAs (endorphins and enkephalins). All
contain Met or Leu enkephalin at
N-terminus Biosynthesised from three inactive
protein precursors (proenkephalin, prodynorphin
and pro-opiomelanocortin) Inactived by peptidase
enzymes in vivo (orally inactive) - hydrolysed
between Tyr and Gly
H-Tyr-Gly-Gly-Phe-Met-OH
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SAR Tyrosine essential for activity (phenol ring
and N) Phenol ring of Tyr thought to be
equivalent to phenol ring of morphine Tyr
nitrogen thought to be equivalent to morphine
amine Aromatic ring of Phe important (additional
interaction)
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ANALOGUES
AIM To synthesise analogues which are stable to
peptidases and which would be orally
active STRATEGY Replace non essential amino
acids with unnatural AAs or D-AAs to make
enkephalin unrecognisable to peptidase enzymes
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EXAMPLES
H-(L-Tyr)-(D-AA)-Gly-(NMe-L-Phe)-(L-Met)-OH
Resistant to peptidase. Orally active
(N,N-Diallyl-L-Tyr)-aib-aib-(L-Phe)-(L-Met)-OH
aib a-aminobutyric acid
Antagonist to the gamma receptor