Opioid dipeptide 5-antagonist

DTOH is an active 5-opioid dipeptide antagonist upon peripheral administration due to a combination of its unique physiochemical properties (lipophilic, water-solubility, stability). 

Page D, McClory A, Mischki T, Schmidt R, Butterworth J, St-Onge S, Labarre M, Payza K, Brown W. Novel Dmt-Tic dipeptide analogues as selective delta-opioid receptor antagonists. Bioorg Med Chem Lett 2000 10 167-170. 

Dipeptidic, (IV), and tripepitidic conjugates effective in traversing the blood-brain barrier were prepared by Lazarus (5) and used as 8 opioid receptor antagonists. 

In 1995 the dipeptide H-Dmt-Tic-OH was reported to be a 6-opioid antagonist with unprecedented 6-receptor affinity (K = 0.022 nM) and 6 receptor selectivity (Kf/Kf = 150,000) [47]. However, in a direct comparison under identical assay conditions, this compound showed about 30 times lower 6-antagonist potency and 6 times lower 6-receptor selectivity... 

The three prototype mixed p agonist/S antagonists described in this chapter have excellent potential as analgesics with low propensity to produce tolerance and dependence. The pseudotetrapeptide DIPP-NH2[ ] has already been shown to produce a potent analgesic effect, less tolerance than morphine, and no physical dependence upon chronic administration. In preliminary experiments, the tetrapeptides DIPP-NH2 and DIPP-NH2[T] were shown to cross the BBB to some extent, but further structural modifications need to be performed in order to improve the BBB penetration of these compounds. The Tyr-Tic dipeptide derivatives can also be expected to penetrate into the central nervous system because they are relatively small, lipophilic molecules. In this context, it is of interest to point out that the structurally related dipeptide H-Dmt-D-Ala-NH-(CH2)3-Ph (SC-39566), a plain p-opioid agonist, produced antinociception in the rat by subcutaneous and oral administration [72], As indicated by the results of the NMR and molecular mechanics studies, the conformation of the cyclic p-casomorphin analogue H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-] is stabilized by intramolecular hydrogen bonds. There-... 

The dipeptide H-Dmt-Tic-OH has been reported to be an ultraselec-tive 6- opioid antagonist (K = 0.022 nM, K /Kf= 150,773) [46], However, subsequent evaluations of this compound indicated that it had much lower 6-receptor binding affinity and much lowe 6-receptor selectivity than originally... 

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