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(CH2)n],3- or 6-R-2(1H)-pyrazinone (n = 1–4). 3-[H-Dmt-NH-(CH2)4]-6-β-phenethyl-5-methyl-2(1H)-pyrazinone 11 bound to μ-opioid receptors with high affinity (Kiμ = 0.13 nM; Kiδ/Kiμ = 447) with μ-agonism (GPI IC50 = 15.9 nM) and weak δ-antagonism (MVD pA2 = 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.