Bioorganic & Medicinal Chemistry Letters 2006-09-15

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

Ravil R Petrov, Ruben S Vardanyan, Yeon S Lee, Shou-wu Ma, Peg Davis, Lucinda J Begay, Josephine Y Lai, Frank Porreca, Victor J Hruby

Index: Bioorg. Med. Chem. Lett. 16(18) , 4946-50, (2006)

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Abstract

An enkephalin analogue coupled to 'aminofentanyl' has been synthesized and tested for biological activities at the mu and delta 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 beta-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 delta and mu opioid receptors) and bioactivity (34.9 nM in MVD and 42 nM in GPI/LMMP bioassays).