Design and synthesis of opioidmimetics containing 2',6'-dimethyl-L-tyrosine and a pyrazinone-ring platform.
Twelve 2',6'-dimethyl-L-tyrosine (Dmt) analogues linked to a pyrazinone platform were synthesized as 3- or 6-[H-Dmt-NH(CH(2))(n)],3- or 6-R-2(1H)-pyrazinone (n=1-4). 3-[H-Dmt-NH-(CH(2))(4)]-6-beta-phenethyl-5-methyl-2(1H)-pyrazinone 11 bound to mu-opioid receptors with high affinity (K(i)mu=0.13 nM; K(i)delta/K(i)mu=447) with mu-agonism (GPI IC(50)=15.9 nM) and weak delta-antagonism (MVD pA(2)=6.35). Key factors affecting opioid affinity and functional bioactivity are the length of the aminoalkyl chain linked to Dmt and the nature of the R residue. These data present a simplified method for the formation of pyrazinone opioidmimetics and new lead compounds.
Shiotani
Kimitaka
K
The Graduate School of Food and Medicinal Sciences, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan.
Li
Tingyou
T
Miyazaki
Anna
A
Tsuda
Yuko
Y
Yokoi
Toshio
T
Ambo
Akihiro
A
Sasaki
Yusuke
Y
Bryant
Sharon D
SD
Lazarus
Lawrence H
LH
Okada
Yoshio
Y
D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D018716:Molecular Mimicry; D011719:Pyrazines / Q000737:chemistry*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry