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SYNTHESIS AND BIOLOGICAL ACTIVITY OF ENKEPHALIN ANALOGS
Abstract
The synthesis and biological activity of two types of enkephalin analogs are reported: those in which the C-terminal carboxylic acid group was replaced by a chloromethyl ketone, and those in which the C-terminus was replaced by lysine, or a derivative of lysine. The substitution of the terminal carboxyl group of leucine enkephalin and D-Ala('2)-leucine enkephalin with a chloromethyl ketone uniformly increased the potency in the guinea pig ileum assay by a factor of six. The chloromethyl ketones were also more potent in inhibiting the stereospecific binding of {('3)H}-naloxone to opiate receptors in the rat brain. While the chloromethyl ketone analogs had the potential to act as irreversible agonists it was not clear from the present studies that such binding did indeed occur. The increased activity of these derivatives was related to the increased lipophilic character of the peptide C-terminus. Since decreasing the hydrophilic character of C-6, -7 and -8 of the C-ring of morphine leads to increased analgesic activity, the increased activity of the more hydrophobic chloromethyl ketones supports the suggestion that the Leu('5) carboxyl group of enkephalins overlaps the 6-hydroxyl group of morphine in the region of the C-ring. The biological activity of analogs substituted at the C-terminus with lysine, or a derivative of lysine containing either a formyl-, acetyl-, octanoyl-, or carbobenzyoxy-group attached to the (epsilon)-amino function, confirmed the importance of a hydrophobic group at that position. The most potent analog, D-Ala('2), N-(epsilon)-carbobenzyoxy-Lys('5)-enkephalin, was found to be almost three times more potent than the corresponding leucine enkephalin compound in the guinea pig ileum assay. These studies show that relatively large groups can be accommodated at the terminal position, without loss of activity. The synthesis of an LHRH precursor, in which the amino acid side chain functional groups are blocked by protecting groups, is also reported. Some progress in the preparation of the diazomethyl and chloromethyl ketone analogs of LHRH is discussed.
Subject Area
Organic chemistry
Recommended Citation
PELTON, JOHN TOM, "SYNTHESIS AND BIOLOGICAL ACTIVITY OF ENKEPHALIN ANALOGS" (1982). ETD collection for University of Nebraska-Lincoln. AAI8227034.
https://digitalcommons.unl.edu/dissertations/AAI8227034