Identification of an opioid kappa receptor subtype-selective N-substituentfor (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine

A three-component library of compounds was prepared in parallel using multi ple simultaneous solution-phase synthetic methodology. The compounds were b iased toward opioid receptor antagonist activity by incorporating (+)-(3R,4 R)-dimethyl-4-(3-hydroxyphenyl)piperidine (a potent, nonselective opioid pu re antagonist) as one of the monomers. The other two monomers, which includ ed N-substituted or unsubstituted Boc-protected amino acids and a range of substituted aryl carboxylic acids, were selected to add chemical diversity. Screening of these compounds in competitive binding experiments with the k appa opioid receptor selective ligand [H-3]-U69,593 led to the discovery of a novel kappa opioid receptor selective ligand, N-{(2'S)-[3-(4-hydroxyphen yl)propanamido]-3'-methylbutyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl) -4-(3- hydroxyphenyl)piperidine (8, RTI-5989-29). Additional structure-activity re lationship studies suggested that 8 possesses Lipophilic and hydrogen-bondi ng sites that are important to its opioid receptor potency and selectivity. These sites appear to exist predominantly within the kappa receptor since the selectivity arises from a 530-fold loss of affinity of 8 for the mu rec eptor and an 18-fold increase in affinity for the kappa receptor relative t o the mu-selective ligand, (+)-N-[trans-4-phenyl-2-butenyl]-(3R,4R)-dimethy l-4-(3-hydroxyphenyl)piperidine (5a). The degree of selectivity observed in the radioligand binding experiments was not observed in the functional ass ay. According to its ability to inhibit agonist stimulated binding of [S-35 ]GTP gamma S at all three opioid receptors, compound 8 behaves as a mu/kapp a opioid receptor pure antagonist with negligible affinity for the delta re ceptor.