New structural concepts for narcotic antagonists defined in a 4-phenylpiperidine series

Identification of the First trans-(3R,4R)- Dimethyl-4-(3-hydroxyphenyl)piperidine Derivative To Possess Highly Potent and Selective Opioid κ Receptor Antagonist Activity

“…Thus, while only N-allyl and N-cyclopropylmethyl substituents exhibit potent pure antagonist activity in the oxymorphone series (3a,b), all N-substituted derivatives of trans- (3,4)-dimethyl-4-(3-hydroxyphenyl)piperidine, thus far reported, show antagonist activity. 7,8 Recently we reported the discovery of 9 as the first trans-(3,4)-dimethyl-4-(3-hydroxyphenyl)piperidine analogue 11 to display a preference for the opioid κ receptor. Obtained from the screening of libraries biased for opioid antagonist activity through incorporation of trans-(3,4)-dimethyl-4-(3-hydroxyphenyl)piperidine into each ligand, compound 9 (RTI-5989-29) was found to be κ selective in binding but not in functional assays.…”

Kappa-opioid receptor ligands

“…Carroll et al at Research Triangle Institute have developed selective KOR antagonists [56,57,110] within the trans-(3,4)-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonists discovered by Zimmerman et al [58]. The member of this series with a p-hydroxy-dihydrocinnamyl N-substituent (18) had been found previously to show selectivity for the KOR in binding but not in functional assays.…”

Alvimopan for postoperative ileus

“…20 Substitution of the piperidine ring at the 3-position accounts for its ability to antagonize opioid receptors. 20 Alvimopan has a high affinity for m-opioid receptors (dissociation constant K i = 0.77 nmol/L) and lower affinities for k-and d-receptors (K i = 40 and 4.4 nmol/L, respectively).…”