Two recent developments of
opioid peptide-based
analgesics are reviewed. The first part of the review discusses the
dermorphin-derived, cationic-aromatic tetrapeptide H-Dmt-D-Arg-Phe-Lys-NH(2) ([
Dmt(1)]DALDA, where Dmt indicates 2',6'-dimethyltyrosine), which showed subnanomolar
mu receptor binding affinity, extraordinary
mu receptor selectivity, and high mu agonist potency in vitro. In vivo, [
Dmt(1)]DALDA looked promising as a spinal
analgesic because of its extraordinary antinociceptive effect (3000 times more potent than
morphine) in the mouse tail-flick assay, long duration of action (4 times longer than
morphine), and lack of effect on respiration. Unexpectedly, [
Dmt(1)]DALDA also turned out to be a potent and long-acting
analgesic in the tail-flick test when given subcutaneously (s.c.), indicating that it is capable of crossing the blood-brain barrier. Furthermore, little or no cross-tolerance was observed with s.c. [
Dmt(1)]DALDA in
morphine-tolerant mice. The second part of the review concerns the development of mixed mu agonist/delta antagonists that, on the basis of much evidence, are expected to be
analgesics with a low propensity to produce tolerance and physical dependence. The prototype pseudopeptide H-Dmt-TicPsi[CH(2)NH]
Phe-Phe-NH(2) (
DIPP-NH(2)[Psi], where
Tic indicates 1,2,3,4-
tetrahydroisoquinoline-3-
carboxylic acid) showed subnanomolar mu and
delta receptor binding affinities and the desired mu agonist/delta antagonist profile in vitro.
DIPP-NH(2)[Psi] produced a potent
analgesic effect after intracerebroventricular administration in the rat tail-flick assay, no physical dependence, and less tolerance than
morphine. The results obtained with
DIPP-NH(2)[Psi] indicate that mixed mu agonist/delta antagonists look promising as
analgesic drug candidates, but compounds with this profile that are systemically active still need to be developed.