Michael Edward Flaugh

5-HT1F receptor agonists inhibit neurogenic dural inflammation in guinea pigs.

THE serotonin (5-HT) receptor subtype mediating inhibition of neurogenic dural inflammation in guinea pigs was investigated using a series of serotonin agonists with differing affinities for the 5-HT1B, 5-HT1D and 5-HT1F receptors. When agonist potencies for inhibiting neurogenic inflammation were compared with affinities for these receptor subtypes, a significant positive correlation was seen only with the 5-HT1F receptor. The potency of agonists in inhibiting adenylate cyclase in cells transfected with human 5-HT1F receptor was also highly correlated with their potency in the animal model of migraine. In situ hybridization demonstrated 5-HT1F receptor mRNA in guinea pig trigeminal ganglion neurons. These data suggest that the 5-HT1F receptor is a rational target for migraine therapeutics.

Characterization of LY344864 as a pharmacological tool to study 5-HT1F receptors: Binding affinities, brain penetration and activity in the neurogenic dural inflammation model of migraine

LY344864 is a selective receptor agonist with an affinity of 6 nM (Ki) at the recently cloned 5-HT1F receptor. It possesses little affinity for the 56 other serotonergic and non-serotonergic neuronal binding sites examined. When examined for its ability to inhibit forskolin-induced cyclic AMP accumulation in cells stably transfected with human 5-HT1F receptors, LY344864 was shown to be a full agonist producing an effect similar in magnitude to serotonin itself. After an intravenous dose of 1 mg/kg, rat plasma LY344864 levels declined with time whereas brain cortex levels remained relatively constant for the first 6 hours after injection. Oral and intravenous LY344864 administration potently inhibited dural protein extravasation caused by electrical stimulation of the trigeminal ganglion in rats. Taken together, these data demonstrate that LY344864 is a selective 5-HT1F receptor agonist that can be used to explore both the in vitro and in vivo functions of this receptor.

Inhibition of luteinizing hormone release and ovulation by 6-chloro- and 6-fluoromelatonin.

The effects of 6-chloromelatonin and 6-fluoromelatonin on ovulation and LH and prolactin release in rats were determined. Both halogenated melatonin analogs were more potent ovulation blockers than melatonin. The halogenated melatonin analogs inhibited the ovulatory surge of luteinizing hormone (LH) but did not alter the proestrous prolactin surge, nor did they alter basal serum levels of LH or prolactin. The plasma half-life of 6-chloromelatonin in rats and rhesus monkeys was 27 min compared to 11 min for melatonin. The results indicate that 6-chloromelatonin is a melatonin agonist with greater metabolic stability than melatonin.