Sedative potency and 2-[125I]iodomelatonin binding affinity of melatonin analogues

Melatonin (5-methoxyN-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 IV). 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 IP), but not melatonin (10 mg/kg IP), was blocked by pretreatment with the benzodiazepine antagonist, flumazenil (10 mg/kg IP). Similarly, an increase in pentobarbitone sleeping time produced by the aminoalkylindole cannabinoid receptor agonist, WIN 55212-2 (0.5 mg/kg IP), but not that produced by melatonin (10 mg/kg IP) was reduced by the cannabinoid receptor antagonist WIN 56098 (5 mg/kg IP). 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.