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 μ-receptor affinity (Kiμ; 7.58 nM) comparable to that of morphine, while the Dmt derivatives exhibited considerably higher affinity (Kiμ; 0.021–0.051 nM) with corresponding agonism (IC50 = 1.79–4.93 nM). Interestingly one compound (m = 4, n = 3) revealed modest δ-opioid agonism; the converse analogue (m = 3, n = 4), however, was inactive in MVD assay.