Amino acids and peptides. LVI. Synthesis of pyrazinone ring-containing opioid mimetics and examination of their opioid receptor binding activity

Cyclization of dipeptidyl chloromethyl ketones gave 6-(4-aminobutyl)-3-carb oxyethyl-5-methyl-2(1H)-pyrazinone (3), 3-(4-aminobutyl)-6-carboxyethyl-5-m ethyl-2(1H)-pyrazinone (6), and 3,6-bis(4-aminobutyl)-5-methyl-2(1H)-pyrazi none (15), Using above pyrazinone derivatives, three opioid mimetics were p repared (III-V). Derivatives containing 3 and 6 demonstrated weak mu and de lta-opioid receptor affinities ranging from 1.6 mM to 4.1 mM while the opio id mimetic containing derivative 15 displayed higher mu-opioid receptor bin ding affinity (K-i mu = 61 nM) and selectivity (K-i mu/K-i delta = 31). (C) 1999 Elsevier Science Ltd. All rights reserved.