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.
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.
Shiotani
Kimitaka
K
The Graduate School of Food and Medicinal Sciences, Kobe Gakuin University, Kobe 651-2180, Japan.
Li
Tingyou
T
Miyazaki
Anna
A
Tsuda
Yuko
Y
Bryant
Sharon D
SD
Ambo
Akihiro
A
Sasaki
Yusuke
Y
Lazarus
Lawrence H
LH
Okada
Yoshio
Y
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
D009292:Narcotic Antagonists; D011719:Pyrazines; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D014443:Tyrosine