Synthesis and evaluation of 3-aminopropionyl substituted fentanyl analogues for opioid activity

An enkephalin analogue coupled to ‘aminofentanyl’ has been synthesized and tested for biological activities at the μ and δ opioid receptors. Aminofentanyl which represents a structural derivative of fentanyl has been synthesized by acylation of 1-(2-phenethyl)-4-(N-anilino)piperidine with phthaloyl protected β-alaninyl chloride in the presence of DIPEA, followed by deprotection with hydrazine hydrate. Aminofentanyl has also been successfully acylated with ethyl isocyanate, various acid anhydrides, to further investigate structure–activity relationships of these new fentanyl derivatives. Among the new derivatives compound 7 which carries a Tyr-d-Ala-Gly-Phe opioid message sequence showed good opioid affinity (1 nM at both δ and μ opioid receptors) and bioactivity (34.9 nM in MVD and 42 nM in GPI/LMMP bioassays).

Graphical abstractThe synthesis and results of binding affinity and in vitro bioassays of novel fentanyl analogues are reported.Figure optionsDownload full-size imageDownload as PowerPoint slide