of Work: The potent delta-opioid receptor antagonist family of peptides, consisting of the general formula H-Dmt-Tic-NH-CH(R)-R', tested the length and composition of the linker (R), the position of the carboxylate group relative to Bid (1H-benzimidazole-2-yl) (R') at the C-terminus of Tic, the effect of N,N-methylation, presence of various amino acids (R?), and a fluorescent moiety. All the compounds exhibited high delta-opioid receptor affinities (Ki less than 0.1 nM), while high mu-opioid receptor affinities (Ki approximately or less than 1 nM) depended two factors: a non-charged C-terminus, a large hydrophobic or aromatic group (e.g., Bid or Ph). Interesting, a Bid-containing analogue exhibited potent delta-opioid receptor agonism coupled to low to very low mu-opioid receptor agonism. Interestingly, this delta antagonist could be conversted to an agonist by altering the length of the linker and that in turn could be changed back to an antagonist by the addition of a Lys(Z) group. The fluorescent derivative proved to be highly selective (greater than 4,000) for the delta-opioid receptor and was a non-competitive or irreversible antagonist; pretreatment of the tissue in vitro or in situ with naltrindole abolished at least 90% of its activity. (These data were patented and licencing is being discussed.) The data verified that linker chirality is unimportant, a negative charge and N,N-methylation inhibit interaction toward mu-opioid receptors; linker length is critical for the appearance of delta agonist or antagonist activity. Futhermore, Dmt is the key residue for all these activities. Synthetic Dmt-containing analogues contained bis-Dmt separated by alkyl chains or alkyl-pyrazinone had high mu-opioid receptor affinities (Ki less than 0.1 nM), potent functional bioactivity in isolated tissue assays (Ke = 3-5 nM)and in vivo against morphine standard; however, analogues containing Dmt and alkyl-pyrazinone ring compounds were five-fold more potent to produce analgesia. In terms of the analogues of endomorphin, Dmt again enhanced affinity and bioactivity by orders of magnitude, permitting the formation of dual acting delta- and mu-opioid receptor agonsits. Studies verified that Dmt was the essential amino acid that interacted within the mu-opioid receptor; although when coupled to other residues, it also enhanced delta-associated affinity, but it is primarily a mu-selective residues.
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