Opioid peptides and their
G-protein-coupled receptors (delta, kappa, mu) are located in the central nervous system and peripheral tissues. The
opioid system has been studied to determine the intrinsic mechanism of modulation of
pain and to develop uniquely effective
pain-control substances with minimal abuse potential and side effects. Two types of endogenous
opioid peptides exist, one containing Try-Gly-
Gly-Phe as the message domain (
enkephalins,
endorphins,
dynorphins) and the other containing the
Tyr-Pro-
Phe/Trp sequence (endomorphins-1 and -2).
Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2), which has high
mu receptor affinity (Ki = 0.36 nM) and remarkable selectivity (4000- and 15,000-fold preference over the delta and
kappa receptors, respectively), was isolated from bovine and human brain. In addition,
endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), isolated from the same sources, exhibited high
mu receptor affinity (Ki = 0.69 nM) and very high selectivity (13,000- and 7500-fold preference relative to delta and
kappa receptors, respectively). Both
opioids bind to
mu-opioid receptors, thereby activating
G-proteins, resulting in regulation of gastrointestinal motility, manifestation of antinociception, and effects on the vascular systems and memory. To develop novel
analgesics with less addictive properties, evaluation of the structure-activity relationships of the endomorphins led to the design of more potent and stable
analgesics. Opioidmimetics and
opioid peptides containing the amino acid sequence of the message domain of endomorphins,
Tyr-Pro-
Phe/Trp, could exhibit unique binding activity and lead to the development of new therapeutic drugs for controlling
pain.