Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications

Abstract

Fentanyl and its analogs have been mainstays for the treatment of severe to moderate pain for many years. In this review, we outline the structural and corresponding synthetic strategies that have been used to understand the structure-biological activity relationship in fentanyl-related compounds and derivatives and their biological activity profiles. We discuss how changes in the scaffold structure can change biological and pharmacological activities. Finally, recent efforts to design and synthesize novel multivalent ligands that act as mu and delta opioid receptors and NK-1 receptors are discussed.

Figure 1

Fentanyl and major fentanyl analogs.

Figure 2

Approaches to the synthesis of fentanyl.

Figure 3

Modifications of the structure of fentanyl.

Figure 4

Synthesis of perhydroazepine analogs of fentanyl.

Figure 5

Methyl-substituted fentanyls.

Figure 6

Synthesis of 4-aryl-fentanyl analogs.

Figure 7

Synthesis of carfentanyl, alfentanil sufentanil, R30490, and their analogs.

Figure 8

Alternative synthesis of 4-acyl- fentanyls from corresponding acids.

Figure 9

Synthesis of 4-acyloxymethyl- fentanyls.

Figure 10

Examples of ‘ring-closed’ analogs of fentanyl.

Figure 11

One more example of ‘ring-closed’ analogs of fentanyl – indolylpiperidines.

Figure 12

Synthesis of series of pyridoindoles a benzo[a]-quinolizidine derivatives of fentanyl.

Figure 13

Synthesis of isothiocyanate derivatives of fentanyl.

Figure 14

Replacement of 2-arylethylsubstituents at piperidine ring.

Figure 15

Bivalent ligands based on fentanyl.

Figure 16

Functionalized fentanyls for the synthesis of bivalent ligands.

Figure 17

Newly created bivalent ligands based on fentanyl.

Figure 18

Attempts to synthesize fentanyl/adjuvant bivalent compounds.

Figure 19

One other attempt to synthesize fentanyl/δ-agonist bivalent compounds.

Figure 20

Phenylethyl moiety present in all classes of opioids.