Stereochemical requirements for pseudoirreversible inhibition of opioid mu receptor binding by the 3‐methylfentanyl congeners, RTI‐46144 and its enantiomers: Evidence for different binding domains

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Abstract
Fentanyl and its congeners are of interest not only because of their clinical applications, but also because certain members of this series of opioid analgesics exhibit unique properties, such as acting as pseudoirreversible inhibitors of μ receptor binding, both in vitro and in vivo. Previous studies showed that pretreatment of membranes with (+)‐cis‐3‐methylfentanyl resulted in a lower affinity interaction of [3H]ohmefentanyl with the μ binding site, as well as an increased dissociation rate. The present study was undertaken to determine the stereochemical requirements for pseudoirreversible inhibition of μ receptor binding using the methylfentanyl congeners, (±)‐cis‐N‐[1‐(2hydroxy‐2‐phenylethyl)‐3‐methyl‐4‐piperidyl]‐N‐phenylpropanamide HCI (RTI‐4614‐4) and its four resolved enantiomers. A R configuration of the 2‐hydroxy group was essential for high affinity binding and pseudoirreversible inhibition. The two enantiomers with this configuration, lb (2R, 3R,4S)‐N‐[1‐(2‐hydroxy‐2‐phenylethyl)‐3‐methyl‐4‐piperidyl]N‐phenylpropanamide oxalate) and lc ((2R, 3S,4R)‐N‐[1‐(2‐hydroxy‐2‐phenylethyl)‐3methyl‐4‐piperidyl]‐N‐phenylpropanamide HC1), acted as pseudoirreversible inhibitors of the μ receptor as labeled with [3H ][D‐Ala2‐McPhe4, Gly‐ol5]enkephalin, [3H]fentanyl or [3H]etorphine. RTI‐4614‐4, lb, and 1c decreased the Bmax of [3H][D‐Ala2‐MePhe4, Glyol5]enkephalin binding sites without altering the dissociation rate. These drugs had a lesser effect on steady‐state [3H]fentanyl and [3H]etorphine binding but did produce statistically significant changes in the parameters of the two‐component dissociation model, which accurately described the dissociation of these [3H]ligands. Viewed collectively, these data indicate that the mechanism of the pseudoirreversible inhibition appears to depend on the radioligand used to label the μ receptor. To explain these data, a pseudoallosteric model is proposed that postulates that certain μ ligands bind to different domains of the drug recognition site of the μ receptor and that the prebinding of pseudoirreversible inhibitors to the recognition site changes the domains available to a radioligand, leading to alterations in steady‐state binding levels and dissociation kinetics. © 1993 Wiley‐Liss, Inc. 1 This article is a US government work and as such, is in the public domain in the United States of America.

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