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This version is made available in accordance with publisher policies. Please cite only the published version using the reference above. 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 signalling 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, whilst 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.