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

• Published in: Journal of psychopharmacology (Oxford) 2013-02, Vol.27 (2), p.192-202
• Main Authors: Casal-Dominguez, Joseph J, Clark, Mary, Traynor, John R, Husbands, Stephen M, Bailey, Sarah J
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Analgesics - pharmacology; Animals; Antagonists; Anxiety; Anxiety - metabolism; Anxiety - physiopathology; Anxiolytics; Behavior, Animal - drug effects; Biological and medical sciences; Depression; Depression - metabolism; Depression - physiopathology; Diuresis; Guinea Pigs; Ileum; Ligands; Male; Medical sciences; Mice; Mood; Mood disorders; Naltrexone - analogs & derivatives; Naltrexone - chemistry; Naltrexone - pharmacology; Naltrindole; Narcotic Antagonists - pharmacology; Neuropharmacology; Opioid receptors; Pain perception; Pharmacodynamics; Pharmacology. Drug treatments; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rats; Rats, Wistar; Receptors, Opioid, kappa - antagonists & inhibitors; Receptors, Opioid, kappa - metabolism; Receptors, Opioid, mu - antagonists & inhibitors; Receptors, Opioid, mu - metabolism
• ISSN: 0269-8811; 1461-7285
• DOI: 10.1177/0269881112464828

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.