WIN-56098

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.

Six novel aminoalkylindole analogs, related structurally to the dual cyclooxygenase inhibitor and nonopioid analgesic pravadoline, were evaluated in the mouse to determine whether their pharmacol. profile of activity was similar to that exhibited by Δ⁹-tetrahydrocannabinol (Δ⁹-THC).Analog I (C₂-H; C₃-methyoxy-benzoyl) reduced locomotion, but had no other effects (hypothermia, antinociception or ring-immobility) up to 21 μmol/kg.Analogs II and III (C₃-naphthoyl; C₂-H and C₂-Me, resp.) possessed all properties exhibited by Δ⁹-TCH with ED₅₀ values ranging from 0.68 to 18 μmol/kg.Analog IV (C₂-methyl; C₃-anthroyl) was devoid of activity.Stereoselectivity was demonstrated by the fact that (+)-WIN-55,212 (one isomer of a semirigid derivative possessing C₂-H and C₃-naphthoyl substituents) was moderately potent in all tests (ED₄₀ values ranging from 0.25-23 μmol/kg), but (-)-WIN-55,212 was inactive up to 57 μmol/kg.Active aminoalkylindole compounds were generally least effective in the production of hypothermia.Analogs were also evaluated for their ability to produce Δ⁹-THC-like discriminative stimulus effects in rats.The ED₅30 for Δ⁹-THC as a discriminative stimuli for this model was 1.9 μmol/kg.Analog II and III and (+)-WIN-55,212 produced Δ⁹-THC-like discriminative effects with ED₅₀ values ranging from 0.33 to 4.3 μmol/kg, whereas analogs I, IV and (-)-WIN-55,212 did not.Although reported to be cannabinoid receptor antagonists in vitro, neither analog I, analog IV nor (-)-WIN-55,212 (at 20 μmol/kg) antagonized the in vivo pharmacol. effects of Δ⁹-THC in the mouse or rat.These results suggest that this class of compounds, although structurally unrelated to the cannabinoids, produced cannabimimetic activity in vivo, and do so in a stereoselective fashion.Yet these data fail to provide evidence for the inactive aminoalkylindole analogs possessing Δ⁹-THC antagonist properties.