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Identification of an opioid kappa receptor subtype-selective N-substituent for (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine.
J Med Chem. 1998 Dec 17; 41(26):5188-97.JM

Abstract

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 kappa opioid receptor selective ligand [3H]U69,593 led to the discovery of a novel kappa 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 kappa receptor since the selectivity arises from a 530-fold loss of affinity of 8 for the mu receptor and an 18-fold increase in affinity for the kappa receptor relative to the mu-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]GTPgammaS at all three opioid receptors, compound 8 behaves as a mu/kappa opioid receptor pure antagonist with negligible affinity for the delta receptor.

Authors+Show Affiliations

Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

9857089

Citation

Thomas, J B., et al. "Identification of an Opioid Kappa Receptor Subtype-selective N-substituent for (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine." Journal of Medicinal Chemistry, vol. 41, no. 26, 1998, pp. 5188-97.
Thomas JB, Fall MJ, Cooper JB, et al. Identification of an opioid kappa receptor subtype-selective N-substituent for (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine. J Med Chem. 1998;41(26):5188-97.
Thomas, J. B., Fall, M. J., Cooper, J. B., Rothman, R. B., Mascarella, S. W., Xu, H., Partilla, J. S., Dersch, C. M., McCullough, K. B., Cantrell, B. E., Zimmerman, D. M., & Carroll, F. I. (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), 5188-97.
Thomas JB, et al. Identification of an Opioid Kappa Receptor Subtype-selective N-substituent for (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine. J Med Chem. 1998 Dec 17;41(26):5188-97. PubMed PMID: 9857089.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of an opioid kappa receptor subtype-selective N-substituent for (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine. AU - Thomas,J B, AU - Fall,M J, AU - Cooper,J B, AU - Rothman,R B, AU - Mascarella,S W, AU - Xu,H, AU - Partilla,J S, AU - Dersch,C M, AU - McCullough,K B, AU - Cantrell,B E, AU - Zimmerman,D M, AU - Carroll,F I, PY - 1998/12/19/pubmed PY - 1998/12/19/medline PY - 1998/12/19/entrez SP - 5188 EP - 97 JF - Journal of medicinal chemistry JO - J Med Chem VL - 41 IS - 26 N2 - 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 kappa opioid receptor selective ligand [3H]U69,593 led to the discovery of a novel kappa 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 kappa receptor since the selectivity arises from a 530-fold loss of affinity of 8 for the mu receptor and an 18-fold increase in affinity for the kappa receptor relative to the mu-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]GTPgammaS at all three opioid receptors, compound 8 behaves as a mu/kappa opioid receptor pure antagonist with negligible affinity for the delta receptor. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/9857089/Identification_of_an_opioid_kappa_receptor_subtype_selective_N_substituent_for__+___3R4R__dimethyl_4__3_hydroxyphenyl_piperidine_ L2 - https://doi.org/10.1021/jm980511k DB - PRIME DP - Unbound Medicine ER -