Characterization of BU09059: a novel potent selective κ-receptor antagonist

Abstract

Kappa-opioid receptor (κ) antagonists are potential therapeutic agents for a range of psychiatric disorders. The feasibility of developing κ-antagonists has been limited by the pharmacodynamic properties of prototypic κ-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 κ-antagonists was amenable to incorporation of a potentially metabolically labile group, while retaining good affinity and selectivity for the κ-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 κ-receptor, with 15-fold and 616-fold selectivity over μ- and δ-receptors, respectively. In isolated tissues, BU09059 was a potent and selective κ-antagonist (pA2 8.62) compared with BU09057 (pA2 6.87) and BU09058 (pA2 6.76) which were not κ-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 κ-antagonist norBNI. These data show that a new JDTic analogue, BU09059, retains high affinity and selectivity for the κ-receptor and has a shorter duration of κ-antagonist action in vivo.

Figure 1

Structures of BU09057, BU09058, and BU09059 alongside JDTic and predicted physicochemical properties (ACD/I-Lab-2, accessed via the Royal Society of Chemistry National Chemical Database Service) TPSA: topological polar surface area.

Figure 2

Cumulative concentration–response curves, in the guinea pig ileum for U50,488 and DAMGO (maximal agonist concentrations 1 μM), in the presence of increasing concentrations of BU09057 (A, B), BU09058 (C, D), and BU09059 (E, F). Apart from BU09059, all ligands tested caused rightward parallel shifts in the concentration response curves of both U50,488 and DAMGO. Results are expressed as the mean percentage of the maximum response induced by the agonist ± SEM, n = 4 tissues.

Figure 3

Cumulative concentration–response curves, in the mouse vas deferens, for DAMGO (maximal agonist concentration 2 μM) (A) and DPDPE (maximal agonist concentration 20 nM) (B), in the presence of high concentrations of BU09059. Results are expressed as the mean percentage of the maximum response induced by the agonist ± SEM, n = 4 tissues.

Figure 4

Ability of the test compounds BU09057, BU09058, and BU09059 to block U50,488-induced antinociception in the tail-withdrawal test. Mice received a single injection of 0.9% (w/v) saline, BU09057 (A), BU09058 (B), BU09059 (C), and norBNI (D) at both 3 mg/kg (□) and 10 mg/kg (■), and tail-withdrawal latency measured at intervals up to 21 days post injection. U50,488 (10 mg/kg) was injected on each test occasion, 30 min prior to measuring tail-withdrawal latency. Data are expressed as mean percentage maximum possible effect (%MPE) ± SEM, n = 8 per treatment group.