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). Keywords Fentanyl derivatives; Opioid agonists; Enkephalin analogueDepending on their nature all opiates can be broadly divided into two categories: non-peptide and peptide based. Morphine which occurs in nature represents one of the most efficient analgesic drugs among the non-peptide based opiates. Endogenous opioid peptides such as endomorphins, enkephalins, and dynorphins occurring naturally in the brain represent the second class of opiates. The latter function as both neuromodulators and hormones, and are responsible for a broad spectrum of physiological effects. A common feature of these two classes of opiates is their binding to the three recognized opioid receptor types: μ, δ,and κ. A tremendous amount of synthetic work was done to alter the potency, selectivity, and bioavailability of these both classes of opioids.The class of compounds known as 4-anilidopiperidines represent the most powerful synthetic analgesics, which include fentanyl and related compounds. 1-13 Fentanyl is a well-known μ-selective synthetic analgesic (ED 50 0.011 mg/kg) which is 50-100 times more potent than morphine, has a short duration of action and an onset of action almost immediately after intravenous administration. Fentanyl, sufentanyl, and alfentanyl currently represent the three most popular compounds used for analgesia in clinical practice despite the fact that their use results in side effects such as respiratory depression, physical dependence, and rapid tolerance. 14 An evident gap in the literature regarding incorporation of amino acids and peptides into fentanyl chemistry has encouraged us to investigate replacement of the propionyl fragment of The original idea of incorporating 1-and 2-substituted fentanyl analogues into peptides based on the structural analogy between the aromatic rings of fentanyl and the Tyr 1 and Phe 4 residues of the opioid peptides goes back to the early 1980 with the resulting fentanyl analogues showing very weak or no opioid activity, and that study was limited to 1-and 2-substituted analogues. 15 The ability to incorporate and retain the characteristic high opioid activity of 4-anilidopiperidines into peptides holds numerous possibilities in the area of drug design and their...

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