FOUR DIFFERENT TYPES OF OPIOID PEPTIDES WITH MIXED μ AGONIST/δ ANTAGONIST PROPERTIES

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Abstract
Mixed μ agonist/δ antagonists are thought to have potential as analgesics with low propensity to produce tolerance and dependence. The first balanced μ agonist/δ antagonist was the pseudotetrapeptide H-Dmt-Tic[CH2-NH]Phe-Phe-NH2 (DIPP-NH2[]; Dmt = 2,6-dimethyltyrosine; Tic = tetrahydroisoquinoline-3-carboxylic acid), which showed very high μ agonist potency in the GPI assay, excellent δ antagonist potency in the MVD assay and μ and δ receptor affinities in the subnanomolar range. The dipeptide derivative H-Dmt-Tic-NH-(CH2)3-Ph (Ph = phenyl) displayed similarly high μ and δ receptor affinities and appears to be a mixed partial μ agonist/δ antagonist. Another class of mixed μ agonist/δ antagonists are cyclic -casomorphin analogs containing a 2-naphthylalanine (2-Nal) residue in the 3-position of the peptide sequence, the prototype being H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-]. An analog of this type, H-Dmt-c[-D-Orn-2-Nal-D-Pro-Gly-], also showed balanced μ agonist/δ antagonist potencies in the subnanomolar range. The novel cyclic opioid peptide turned out to be yet another prototype of a mixed μ agonist/δ antagonist.

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