Medicinal Chemistry

brain. Since the genetic code for methionine (AUG) differs by only one base from
one of the leucine codons (CUG), a point mutation or genetic drift may account for this
difference. The ratio of the two enkephalins also varies in different brain regions.
The Goldstein group also isolated from the pituitary gland a larger peptide that
proved to be identical to a fragment of β-lipotropin, a pituitary peptide hormone with
a questionable physiological role. This peptide was called β-endorphin, and was found
to be almost 50 times more analgetic than morphine if injected directly into the
brain. Other endorphins and a smaller peptide, dynorphin, were also found in the pitu-
itary. The heptapeptide dermorphin (5.85) was isolated from the skin of the frog
Phyllomedusa.

5.18.2 Structure–Activity Correlations of Opioid Peptide Hormones

Naturally, many structure–activity investigations have been reported on molecularly
modified enkephalin peptide hormones. Besides increasing opiate activity, the principal
goal of this work is to prevent the rapid hydrolysis between Tyr and Gly, the way in
which all enkaphalins become deactivated. Removing the Tyr^1 from enkephalins or
interfering with its phenolic hydroxyl or amino groups abolishes the activity of these
substances. When the natural L-Tyr^1 is replaced by its D-enantiomer, activity is lost in
the enkephalins as well as the endorphins. On the other hand, replacement of the Gly^2
residue with D-Ala renders the peptide resistant to hydrolysis, to the extent that some
of the synthetic enkephalin analogs retain their activity when taken orally. D-Ala^2
analogs combined with modifications of Met^5 have produced potent derivatives. Met^5 -
amides are also resistant to hydrolysis, and some potent compounds have been discov-
ered among them.

5.18.3 Properties of the Opioid Hormone Receptors

There are various opioid receptors; the three major classes of opioid receptors are mu
(μ), delta (δ) and kappa (κ) receptors. The μreceptor is the principal pain-modulating
site in the CNS, mediating the action of morphine. There is considerable interest in the
κ receptor, which mediates a sedating analgesia with decreased addiction liability and
respiratory depression and which allows for some structural flexibility. Unfortunately,
theκreceptor seems to be coupled to the sigma (σ) receptor, which is implicated in
psychotomimetic and dysphoric side effects.

352 MEDICINAL CHEMISTRY