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Isoteoline is a compound of aporphine structure derived from the alkaloid glaucine. Previous studies with isoteoline have shown antagonistic activity at 5-HT(2C) serotonergic receptors. We have investigated whether isoteoline interacts with 5-HT(1B) receptors. An isolation-induced social behavioural deficit test in mice was used as a model of stimulation of these receptors. The deficit in the behaviour of isolated mice in this experimental procedure was reported to be sensitive to 5-HT(1B)-receptor stimulation, since agonists at these receptors are capable of reversing it. In our study, we used N-(3-trifluoromethylphenyl)piperazine (TFMPP) (2 mg kg(-1)) as a reference agonist at these receptor sites. TFMPP completely restored the normal behaviour of the isolated mice. Its effect was prevented by propranolol (4 mg kg(-1)), a beta-adrenergic receptor antagonist with a high affinity for 5-HT(1B) receptors, which was inactive by itself. When isoteoline was given before TFMPP, it did not prevent the effect of the latter. Given alone at doses of 0.25, 1, 4 or 8 mg kg(-1), isoteoline showed an effect of its own to normalize the behaviour of isolated mice. The effect of isoteoline (1 mg kg(-1), i.p.) was antagonized by pretreatment with propranolol, indicating that it was mediated through stimulation of 5-HT(1B) receptors. Repeated treatment with isoteoline (1 mg kg(-1), 2 x 3 days, i.p.) produced tolerance to its effect and significantly attenuated the effect of TFMPP, when animals were tested 16 h after the last injection. In conclusion, the results provided functional evidence of agonist-like activity of isoteoline at the 5-HT(1B) receptors.

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3,3',4',7-Tetrahydroxyflavone (fisetin) has shown various beneficial bioactivities. This study investigated the metabolism and pharmacokinetics of fisetin, 5-hydroxyflavone (5-OH-flavone), and 7-hydroxyflavone (7-OH-flavone) in male Sprague-Dawley rats. Blood was withdrawn via cardiopuncture and assayed by HPLC before and after hydrolysis with sulfatase and beta-glucuronidase. The results indicated that after intravenous administration of fisetin (10 mg/kg of bw), fisetin declined rapidly and fisetin sulfates/glucuronides emerged instantaneously. When fisetin (50 mg/kg of bw) was given orally, fisetin parent form was transiently present in serum only during the absorption phase, whereas fisetin sulfates/glucuronides predominated. The serum metabolites of fisetin showed less potent inhibition on 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH)-induced hemolysis than fisetin. Following oral administrations of 40 mg/kg of bw of 5-OH-flavone and 7-OH-flavone, the glucuronide of 5-OH-flavone and the sulfate/glucuronide of 7-OH-flavone were found in serum, whereas no traces of parent forms were detected. In conclusion, fisetin and 7-OH-flavone were rapidly and extensively biotransformed into their sulfate/glucuronide, whereas 5-OH-flavone was exclusively metabolized to glucuronide.

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