NEUROPEPTIDES--MOLECULAR MECHANISM OF ACTION

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Summary of Work: Structure-activity studies on highly selective delta-opioid di- and tripeptide antagonists containing Dmt-Tic were modified to enhance membrane permeability. They were modified at N- and C-termini with various hydrophobic constituents that increased biological stability by eliminating cyclization to a diketopiperazines. Crystallization of N,N(dimethyl)Dmt-Tic-OH (George, personal communication)indicated that its structure compared favorably with both H-Dmt-Tic-OH and cyclo(Dmt-Tic); although the cyclic analogue exhibited a unique conformation, its activity was less than linear molecules. N-Alkylation of the N-terminus of Dmt-Tic with methyl groups retained high delta affinity and selectivity, whereas ethyl, piperidine, pyrrolidine, or pyyrole reduced affinity to the 1-2 nM range and decreased selectivity. C-Terminal of H-Dmt-Tic-OH modified with methoxy, hydrazide, methyl amide, tert-butyl amide, tetrazole-5yl or 1-adamantanyl amide reduced delta-selectivity by enhancing mu-affinity. In fact, tert-butyl amide and 1-adamantanyl amide resulted in peptides with dual high affinities (delta and mu). Interestingly, the 1-adamantanyl amide derivative had agonist bioactivities, while the tert-butyl amide was a potent antagonist. Change from Tic to D-Phe in di and pentapeptides produced mu antagonists. New di- and tripeptides with additional aromatic centers are currently being investigated. All in all, these hydrophobic-enhanced delta opioid peptides will have greater application in clinical and therapeutic studies in immunosuppression, combatting drug and alcohol abuse. These di- and tripeptides were issued a U.S. Patent, number 5,780,589 on 14 July 1997.