title: Sedative potency and 2-[125I]iodomelatonin binding affinity of melatonin analogues.
abstract: Melatonin (5-methoxy N-acetyltryptamine), the hormone synthesized and released from the pineal gland each night, has sedative and sleep-promoting effects in experimental animals and man. In the present study, the sedative effect of melatonin and a number of analogues was determined by examining their ability to extend the duration of the loss of righting reflex ("sleeping time") in mice injected with pentobarbitone (50 mg/kg i.v.). All of the analogues tested produced a dose-related (5-20 mg/kg) potentiation of pentobarbitone sleeping time. In radioligand binding assays using 2-[125I]iodomelatonin in chicken brain membranes, all of the analogues were competitive inhibitors. There was no correlation between their ability to inhibit 2-[125I]iodomelatonin binding in chick and sedative potency in the mouse. Potentiation of pentobarbitone sleeping time by diazepam (1 mg/kg i.p.), but not melatonin (10 mg/kg i.p.), was blocked by pretreatment with the benzodiazepine antagonist, flumazenil (10 mg/kg i.p.). Similarly, an increase in pentobarbitone sleeping time produced by the aminoalkylindole cannabinoid receptor agonist, WIN 55212-2 (0.5 mg/kg i.p.), but not that produced by melatonin (10 mg/kg i.p.) was reduced by the cannabinoid receptor antagonist WIN 56098 (5 mg/kg i.p.). These studies confirm that melatonin has sedative activity and show that this action is shared by several structurally-related analogues but does not appear to be mediated by an interaction with benzodiazepine or cannabinoid receptors.
authors.affiliation: Biomedical Sciences Division, King's College London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Sugden
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002645:Chickens; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007457:Iodine Radioisotopes; D008550:Melatonin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051379:Mice; D010424:Pentobarbital / Q000494:pharmacology; D011869:Radioligand Assay; D043882:Receptors, Cannabinoid; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism; D011963:Receptors, GABA-A / Q000187:drug effects; D044094:Receptors, Melatonin; D012890:Sleep / Q000187:drug effects
chemical_list: D006993:Hypnotics and Sedatives; D007457:Iodine Radioisotopes; D043882:Receptors, Cannabinoid; D011956:Receptors, Cell Surface; D011955:Receptors, Drug; D011963:Receptors, GABA-A; D044094:Receptors, Melatonin; D010424:Pentobarbital; D008550:Melatonin