title: Synthesis of 3,6-bis[H-Tyr/H-Dmt-NH(CH2)m,n]-2(1H)pyrazinone derivatives: function of alkyl chain length on opioid activity.
abstract: Dimeric opioid analogues linked to a pyrazinone platform, 3-[Tyr/Dmt-NH(CH2)m]-6-[Tyr/Dmt-NH(CH2)n]-2(1H)-pyrazinone (m, n=3 or 4), were synthesized. The Tyr-containing compound (m=4, n=3) exhibited mu-receptor affinity (K(i)mu; 7.58 nM) comparable to that of morphine, while the Dmt derivatives exhibited considerably higher affinity (K(i)mu; 0.021-0.051 nM) with corresponding agonism (IC50=1.79-4.93 nM). Interestingly one compound (m=4, n=3) revealed modest delta-opioid agonism; the converse analogue (m=3, n=4), however, was inactive in MVD assay.
authors.affiliation: The Graduate School of Food and Medicinal Sciences, Kobe Gakuin University, Kobe 651-2180, Japan.
authors.forename: Kimitaka
authors.initials: K
authors.lastname: Shiotani
authors.forename: Tingyou
authors.initials: T
authors.lastname: Li
authors.forename: Anna
authors.initials: A
authors.lastname: Miyazaki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Bryant
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ambo
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Lazarus
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Okada
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D008956:Models, Chemical; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D009292:Narcotic Antagonists; D011719:Pyrazines; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D014443:Tyrosine