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Fentanyl is a highly potent and clinically widely used narcotic analgesic. The synthesis of its analogs remains a challenge in an attempt to develop highly selective µ-opioid receptor agonists with specific pharmacological properties. In this paper, the use of flexible molecular docking of several specific fentanyl analogs to the µ-opioid receptor model, in order to test the hypothesis that the hydrophobic pocket accommodates alkyl groups at position 3 of the fentanyl skeleton, is described. The stereoisomers of the following compounds were studied: cis- and trans-3-methylfentanyl, 3,3-dimethylfentanyl, cis- and trans-3-ethylfentanyl, cis- and trans-3-propylfentanyl, cis-3-isopropylfentanyl and cis-3-benzylfentanyl. The optimal position and orientation of these fentanyl analogs in the binding pocket of the µ-receptor, explaining their enantiospecific potency, were determined. It was found that the 3-alkyl group of cis-3R,4S and trans-3S,4S stereoisomers of all the active compounds occupies the hydrophobic pocket between TM5, TM6 and TM7, made up of the amino acids Trp318 (TM7), Ile322 (TM7), Ile301 (TM6) and Phe237 (TM5). However, the fact that this hydrophobic pocket can also accommodate the bulky 3-alkyl substituents of the two inactive compounds: cis-3-isopropylfentanyl, and cis-3-benzylfentanyl, indicates that this hydrophobic pocket in the employed receptor model is probably too large. .

Location of the hydrophobic pocket in the binding site of fentanyl analogs in the µ-opioid receptor