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. 2007 Nov 1;17(21):5768-71.
doi: 10.1016/j.bmcl.2007.08.058. Epub 2007 Aug 28.

Design and synthesis of opioidmimetics containing 2',6'-dimethyl-L-tyrosine and a pyrazinone-ring platform

Kimitaka Shiotani  1 , Tingyou Li, Anna Miyazaki, Yuko Tsuda, Toshio Yokoi, Akihiro Ambo, Yusuke Sasaki, Sharon D Bryant, Lawrence H Lazarus, Yoshio Okada
Affiliations

Design and synthesis of opioidmimetics containing 2',6'-dimethyl-L-tyrosine and a pyrazinone-ring platform

Kimitaka Shiotani et al. Bioorg Med Chem Lett. .

Abstract

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.

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Figures

Figure 1
Figure 1
The structure of Dmt-pyrazinone derivatives (1-12)
Scheme 1
Scheme 1
Synthetic method for pyrazinone-ring containing opioidmimetics (1-12). i 4MHCl/dioxane; ii CH3OH, at 60 °C; iii 25%HBr/CH3COOH; iv Boc-Dmt-OH, PyBop, DIPEA.
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