Characterization of BU09059: a novel potent selective ?-receptor antagonist.

ABSTRACT: Kappa-opioid receptor (?) antagonists are potential therapeutic agents for a range of psychiatric disorders. The feasibility of developing ?-antagonists has been limited by the pharmacodynamic properties of prototypic ?-selective antagonists; that is, they inhibit receptor signaling for weeks after a single administration. To address this issue, novel trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl) piperidine derivatives, based on JDTic, were designed using soft-drug principles. The aim was to determine if the phenylpiperidine-based series of ?-antagonists was amenable to incorporation of a potentially metabolically labile group, while retaining good affinity and selectivity for the ?-receptor. Opioid receptor binding affinity and selectivity of three novel compounds (BU09057, BU09058, and BU09059) were tested. BU09059, which most closely resembles JDTic, had nanomolar affinity for the ?-receptor, with 15-fold and 616-fold selectivity over ?- and ?-receptors, respectively. In isolated tissues, BU09059 was a potent and selective ?-antagonist (pA2 8.62) compared with BU09057 (pA2 6.87) and BU09058 (pA2 6.76) which were not ?-selective. In vivo, BU09059 (3 and 10 mg/kg) significantly blocked U50,488-induced antinociception and was as potent as, but shorter acting than, the prototypic selective ?-antagonist norBNI. These data show that a new JDTic analogue, BU09059, retains high affinity and selectivity for the ?-receptor and has a shorter duration of ?-antagonist action in vivo.

SUBMITTER: Casal-Dominguez JJ 

PROVIDER: S-EPMC3963132 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature