title: In vivo and in vitro characterization of naltrindole-derived ligands at the κ-opioid receptor.
abstract: 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 [(3)H]-diprenorphine binding, guanosine-5'-O-(3-[35S]-thio) triphosphate ([(35)S]-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 (K (i) 1.36 ± 0.98 and 0.27 ± 0.08, respectively) and were revealed as potent κ-antagonists (pA(2) 7.43 and 8.18, respectively) and μ-receptor antagonists (pA(2) 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.
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Casal-Dominguez
authors.forename: Mary
authors.initials: M
authors.lastname: Clark
authors.forename: John R
authors.initials: JR
authors.lastname: Traynor
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Husbands
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Bailey
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001007:Anxiety / Q000378:metabolism / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects; D003863:Depression / Q000378:metabolism / Q000503:physiopathology; D006168:Guinea Pigs; D008024:Ligands; D008297:Male; D051379:Mice; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000700:Analgesics; D008024:Ligands; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009271:Naltrexone; C055382:naltrindole