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

A three-component library of compounds was prepared in parallel using multiple simultaneous solution-phase synthetic methodology. The compounds were biased toward opioid receptor antagonist activity by incorporating (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (a potent, nonselective opioid pure antagonist) as one of the monomers. The other two monomers, which included 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 ? opioid receptor selective ligand [3H]U69,593 led to the discovery of a novel ? opioid receptor selective ligand, N-{(2‘S)-[3-(4-hydroxyphenyl)propanamido]-3‘-methylbutyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (8, RTI-5989-29). Additional structure?activity relationship studies suggested that 8 possesses lipophilic and hydrogen-bonding sites that are important to its opioid receptor potency and selectivity. These sites appear to exist predominantly within the ? receptor since the selectivity arises from a 530-fold loss of affinity of 8 for the ? receptor and an 18-fold increase in affinity for the ? receptor relative to the ?-selective ligand, (+)-N-[trans-4-phenyl-2-butenyl]-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (5a). The degree of selectivity observed in the radioligand binding experiments was not observed in the functional assay. According to its ability to inhibit agonist stimulated binding of [35S]GTP?S at all three opioid receptors, compound 8 behaves as a ?/? opioid receptor pure antagonist with negligible affinity for the ? receptor.


Thomas, J., Fall, M., Cooper, J., Rothman, RB., Mascarella, S., Xu, H., ... Carroll, F. (1998). Identification of an opioid kappa receptor subtype-selective N- substituent for (+)-(3R,4R)-dimethyl-4-(3- hydroxyphenyl)piperidine. Journal of Medicinal Chemistry, 41(26), 5188-5197. https://doi.org/10.1021/jm980511k

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