Amino Acids and Peptides. LII. Design and Synthesis of Opioid Mimetics Containing a Pyrazinone Ring and Examinaiton of Their Opioid Receptor Binding Activity

Abstract

An amino group was introduced to the 3 or 6 position of a pyrazinone ring by cyclization of dipeptidyl chloromethyl ketones. Boc-Tyr-OH was coupled with the amino funciton, followed by removal of the Boc group to give pyrazinone ring-containing tyrosine derivatives. Of the various tyrosine derivatives prepared, 5-methyl-6-β-phenethyl-3-tyrosylaminobutyl-2(1H)-pyrazinone exhibited strong binding to the μ-opioid receptor with a K_i value of 55.8 nM and to the δ-opioid receptor with a K_i value of 2165 nM and with a K_iμ/K_iδ value of 0.026.