Neuropeptides--molecular Mechanism Of Action

Environmental Health Sciences

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Abstract

Summary of Work: The delta-opioid receptor anatgonist family of peptides, consisting of the Dmt-Tic pharmacophore, was modified at the C-terminus. This new series of peptides, H-Dmt-Tic-NH-R-R', used various heteroaliphatic ring structures and linkers (spacers) to the C-terminus of Tic. Compounds exhibited high delta affinities (Ki < 0.1 nM) and some gained high mu affinity Ki < 1 nM), indicating an increase by several orders of magnitude relative to H-Dmt-Tic-NH-X, where X = Ala, D-Ala, Asp, Asn, Glu, D-Glu, or Gln. The bioactivity of some Bid-containing analogues had mixied delta antagonism/mu agonism or delta agonism/mu agonism; e.g., H-Dmt-Tic-NH-CH2-Bid had a potent delta agonism (pEC50 = 9.9), which is the first time a delta antagonist, H-Dmt-Tic-OH (pA2 = 9.2) was transformed into a delta agonist. Data verified the following: chirality of the linker is ineffective; a negative charge affects mu affinity; linker length is critical for the appearance of delta agonist or antagonist activity; and C-terminal extension from Bid also affects the acquisition of these activities. Dmt is the key residue for all these activities; however, Tic is responsible for antagonism. The in vivo activity of H-Dmt-Tic-NH-CH2-Bid and H-Dmt-Tic-NH-CH(CH2-Bid)COOH analgesia by hot plate and tail flick tests were about about 15% and 60% of that for delta-2 agonist deltorphin B after icv administration. Two new series of synthetic Dmt-containing analogues formed around the pyrazinone ring or alkyl chains were developed: the later series of simple compounds have very high mu affinities (Ki < 0.1 nM), Ke = 3-5 nM, and equipotent with morphine in vivo while the former are ca. 25 times more potent than morphine.