Synthesis of 36-bisH-Tyr/H-Dmt-NH(CH2)mn-2(1H)pyrazinone derivatives: function of alkyl chain length on opioid activity

摘要

Dimeric opioid analogues linked to a pyrazinone platform, 3-[Tyr-NH(CH2)m]-6-[Tyr-NH(CH2)n]-2(1H)-pyrazinone (n, m = 3 or 4) and their corresponding Dmt derivatives were synthesized. Whereas the Try-containing compounds were essentially inactive, the Dmt derivatives exhibited high affinity for the µ-opioid receptor (Kiµ; 0.021–0.051 nM) with corresponding agonism (IC50 = 1.79–4.93 nM). Interestingly, while one compound (m = 4, n = 3) revealed modest δ-agonism, the converse analogue (m = 3, n = 4) was inactive. The data suggest that the spatial conformation, linker length and covalent bonding position on the pyrazinone ring are important for opioid activity.