Neuropeptides--molecular Mechanism Of Action

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Summary of Work: The potent delta-opioid receptor selective anatgonist consisting of the Dmt-Tic pharmacophore was modified by direct changes at the C-terminus of the dipeptide, in which the protonated nitrogen was either a primary or teriary amine. A new series of opioids was developed containing C-terminal substituents with or without a spacer (linker) between Tic and a third aromatic nucleus; in spite of the C-terminal extension, they all exhibited high delta affinities and in some cases the compounds gained high mu affinity, which increased by orders of magnitude. The bioactivity of six Bid-containing analogues indicated mixied delta antagonism/mu agonism, delta agonism/mu agonism and delta antagonism/mu antagonism. One compound had potent delta agonism (IC50 = 9.9), which is the first time a delta antagonist (pA2 = 9.2) was transformed into a delta agonist. The data verified that delta affinity does not require a negative charge, and that aromaticity and the distance between the third aromatic nucleus and that of Tic is highly critical. The key residue for all these activities was Dmt; although Tic was thought to be responsible for antagonism, its presence in an agonist sheds doubt on this hypothesis. Two new series of synthetic Dmt-containing analogues formed around the pyrazinone ring or alkyl chains are being developed that might provide us with new mu agonists to alleviate cancer-induced pain and post-operative pain.