title: Identification of an opioid kappa receptor subtype-selective N-substituent for (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine.
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.affiliation: Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Thomas
authors.forename: M J
authors.initials: MJ
authors.lastname: Fall
authors.forename: J B
authors.initials: JB
authors.lastname: Cooper
authors.forename: R B
authors.initials: RB
authors.lastname: Rothman
authors.forename: S W
authors.initials: SW
authors.lastname: Mascarella
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.forename: J S
authors.initials: JS
authors.lastname: Partilla
authors.forename: C M
authors.initials: CM
authors.lastname: Dersch
authors.forename: K B
authors.initials: KB
authors.lastname: McCullough
authors.forename: B E
authors.initials: BE
authors.lastname: Cantrell
authors.forename: D M
authors.initials: DM
authors.lastname: Zimmerman
authors.forename: F I
authors.initials: FI
authors.lastname: Carroll
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D008024:Ligands; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: C116538:6,7-diacetylalmuheptolide A; D007783:Lactones; D008024:Ligands; D009292:Narcotic Antagonists; D010880:Piperidines; C116542:RTI 5989-29; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C116537:almuheptolide A