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

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(1 H)-pyrazinone ( n = 1–4). 3-[H-Dmt-NH-(CH 2) 4]-6-β-phenethyl-5-methyl-2(1 H)-pyrazinone 11 bound to μ-opioid receptors with high affinity ( K iμ = 0.13 nM; K i δ/ K iμ = 447) with μ-agonism (GPI IC 50 = 15.9 nM) and weak δ-antagonism (MVD p A 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.