Systematic Study on the Structure-Activity Relationship of Pyrazinone Ring-Containing Bioactive Opioid Ligands

摘要

We previously reported the development of pyrazinone ring-containing analgesics, 3, 6-bis[Dmt-NH-(CH2)_n]-5-methyl-2(lH)pyrazinones (n=l-4), which exhibited considerably potent antinociceptive activity after intracerebroventricular (i.c.v.), subcutaneous (s.c.) and oral (p.o.) administration in mice. These compounds bound to mu-opioid receptors (MOR) with high affinity and high selectivity over delta-opioid receptor (DOR). A rapid and facile procedure of 2(lH)-pyrazinone derivatives from dipeptidyl chloromethyl ketones was developed in our laboratory ; the opioid ligands containing Dmt (2',6'-dimethyl-L-tyrosine) as the functional N-termini were prepared. In this presentation, synthesis of the full set of 3-[Dmt-NH-(CH2)_m]-6-[Dmt-NH-(CH2)_n]-5-methyl-2(lH)-pyrazinones [Fig. 1 (m, n = 1-4)] and their structure-activity relationship are discussed.