Fentanyl conformations

Subramanian, G., Ferguson, D.M. Conformational landscape of selectivity m-opioid agonists in gas phase and in aqueous solution The Fentanyl Series, Drug Design and Discovery 2000, 17, 53-... 

The spirane ring is formed by treating amides derived from 16 with formamide and reducing the product.(20,56) In the solid state the 4-NPh moiety adopts an equatorial rather than an axial conformation in relation to the piperidine ring,(57) akin to the solid and probable solute state conformation of fentanyl, for which there is X-ray<58) and H-nmr evidence (see 20). The activities of the spiranes 19 also provide evidence that anilido phenyl is a- rather than /3-oriented in active conformations of fentanyl derivatives (21). This aromatic feature is confined to the /3-orientation in the bicyclo analogs 22, neither of... 

Fig. 13.9. Molecular models of the potent agonists phenazocine, phenyloripavine, etonitazene, and fentanyl. Rings A and F and the amine nitrogen are drawn in common spatial orientation, the hypothetical agonist conformation of these dings.

A vastly different relationship between the active conformations of fentanyl and pethidine was deduced from a computer matching exercise carried out on these two analgesics (plus morphine) using the basic nitrogen center and three aromatic carbons as reference points.(mi Good matches were... 

Ring conformations are believed to be important in drug activity. For example, experimental evidence suggests that the analgesic fentanyl binds to opiate receptors preferentially in the conformation shown in Fig. 21, where the bulky substituents are positioned equatorially to minimize conformational instability. 

Figure 10. Best fit from conformational matching of morphine and fentanyl...

The preferred conformation of fentanyl and other 4-anilidopiperidines has been examined by X-ray crystallography, NMR, and computational methods (see Refs. 187, 284, 446). In the crystal structure the anilido moiety adopts an equatorial conformation (see 8, Fig. 7.1) (447). Several conformationally con-... 

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