Synthesis and evaluation of 1- and 2-substituted fentanyl analogs for opioid activity

Abstract

We synthesized fentanyl analogues that possess key groups common to the opioid peptides to investigate whether or not these two classes of compounds interact with common subsites on opioid receptors. The design of the analogues was based on the possibility of structural analogy between the two aromatic rings of fentanyl and the Tyr1 and Phe4 residues of the opioid peptides. The synthesized compounds showed very weak or no opioid activity as tested in the electrically stimulated longitudinal muscle of the guinea pig ileum or mouse vas deferens preparations. These results, together with those of reported studies, suggest that fentanyl and the opioid peptides interact with different subsites on either mu or sigma receptors. Studies using the irreversible mu opioid receptor antagonist, beta-funaltrexamine, indicate that fentanyl interacts preferentially with mu opioid receptors.

Studies on 1-(2-phenethyl)-4-(N-propionylanilino)piperidine (fentanyl) and its related compounds. VI. Structure-analgesic activity relationship for fentanyl, methyl-substituted fentanyls and other analogues

“…Fentanyl analogues with a methyl group (e.g., α-methyl, 3-methyl, p-methyl, n-butyryl, and isobutyryl) were synthesized in accordance with previous reports [6,7,[10][11][12][13][14][15].…”

“…These compounds had high potential for abuse, because of their ease of synthesis and high analgesic activity. The structures of fentanyl (1) and 11 synthesized analogues (2-12) examined in this study are shown in Tables 1-4. Although there are a number of reports regarding the analgesic activities of some of these analogues [8][9][10][11][12][13][14][15], there have been only a few reports on the actually abused analogues [8]; there have been no reports on α-methylfentanyl (2), the most widely abused analogue. Furthermore, comparison of their analgesic activities with those of morphine and fentanyl was not described.…”

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

“…Thus, it appears that attachment of a peptide bond to the propionyl moiety of fentanyl encounters unfavorable interactions at the μ-and particularly at δ-opioid binding sites. A comparison of the affinities of compounds presented by Essawi and Portoghese, 15 Montero et al, 34 and ours (4b, 4e, and 7) indicates that propionyl moiety together with phenethyl part of fentanyl play a very important role in opioid receptor binding and activation.…”

“…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 medicinal applications. For example, attachment of the corresponding unit would allow rather simple introduction of opioid activity into any peptide of interest, which can be fruitful for designing multiple ligands.…”

Synthesis of Free and Nα‐Fmoc‐/Nγ‐Boc‐Protected (2S,4S)‐ and (2S,4R)‐4‐Aminopipecolic Acids

“…[15,16,29] Some syntheses of 4-aminopipecolic acids derivatives are known, [28,30,31] but none seems suitable for the synthesis of orthogonally protected 4-aminopipecolic acids 6 and 7.…”