title: Transformation of a kappa-opioid receptor antagonist to a kappa-agonist by transfer of a guanidinium group from the 5'- to 6'-position of naltrindole.
abstract: The importance of the indole scaffold of GNTI 3 in directing its address (5'-guanidinium group) to associate with the Glu297 residue of the kappa-opioid receptor was investigated by the synthesis and biological evaluation of its 4'- (4a), 6'- (4b), and 7'- (4c) regioisomers. The finding that only the 5'-regioisomer (GNTI) possessed potent kappa-opioid antagonist activity and high affinity at kappa-receptors illustrates the importance of the 5'-position in orienting the guanidinium group to the proper recognition locus (Glu 297) for potent kappa-antagonist activity. The discovery that the 6'-regioisomer of GNTI was a potent kappa-agonist, together with the results of site-directed mutagenesis studies that are consistent with association between the 6'-guanidinium group and Glu297, suggest that the transition from an inactive to an active state of the kappa-receptor involves a conformational change of TM6. We propose that association of the 6'-guanidinium group of 4b with Glu297 promotes axial rotational motion of transmembrane helix VI which leads to receptor activation via a conformational change of inner loop 3.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Sharma
authors.forename: R M
authors.initials: RM
authors.lastname: Jones
authors.forename: T G
authors.initials: TG
authors.lastname: Metzger
authors.forename: D M
authors.initials: DM
authors.lastname: Ferguson
authors.forename: P S
authors.initials: PS
authors.lastname: Portoghese
mesh_terms: D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D019791:Guanidine / Q000737:chemistry*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D009271:Naltrexone; C055382:naltrindole; D019791:Guanidine