In vivo and in vitro characterization of naltrindole-derived ligands at the κ-opioid receptor

J. J. Casal-Dominguez, M. Clark, J. R. Traynor, S. M. Husbands, Sarah J. Bailey

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Accumulating evidence supports a role for κ−opioid receptor antagonists in the treatment of mood disorders. Standard κ-antagonists have an unusual pharmacodynamic action, with a single injection blocking receptor signaling for several weeks. Here, we have characterized the κ-selective properties of two ligands, 5’-(2-aminomethyl) naltrindole (5’-AMN) and N-((Naltrindol-5-yl) methyl) pentanimidamide (5’-MABN), to identify whether modifications of the naltrindole side chain produces short-acting κ-antagonists. Opioid receptor binding affinity and activity were assessed using [3H]-diprenorphine binding, guanosine-5’-O-(3-[35S]-thio) triphosphate ([35S]-GTPγS) binding and isolated guinea-pig ileum. Pharmacodynamic profiles of 5’-AMN and 5’-MABN (1–10 mg/kg) were investigated using the tail-withdrawal assay and diuresis. Efficacy was also determined in depression- and anxiety-related behavioral paradigms in CD-1 mice. Both 5’-AMN and 5’-MABN had high affinity for κ−receptors (Ki 1.36±0.98 and 0.27±0.08, respectively) and were revealed as potent κ-antagonists (pA2 7.43 and 8.18, respectively) and μ-receptor antagonists (pA2 7.62 and 7.85, respectively) in the ileum. Contrary to our hypothesis, in vivo, 5’-AMN and 5’-MABN displayed long-lasting antagonist effects in mice, reducing the antinociceptive actions of U50,488 (10 mg/kg) at 28 and 21 days post-injection, respectively. Interestingly, while 5’-AMN and 5’-MABN were not κ-selective, both compounds did show significant antidepressant- and anxiolytic-like effects at 7–14 days post-injection in mice.
Original languageEnglish
Pages (from-to)192-202
Number of pages11
JournalJournal of Psychopharmacology
Issue number2
Early online date31 Oct 2012
Publication statusPublished - Feb 2013


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