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 (K-i ) at the recently cloned 5-HT1F receptor. It possesses little affinity for the 56 other serotonergic and non-serotonergic neuronal binding s ites examined. When examined for its ability to inhibit forskolin-indu ced cyclic AMP accumulation in cells stably transfected with human 5-H T1F receptors, LY344864 was shown to be a full agonist producing an ef fect similar in magnitude to serotonin itself. After an intravenous do se of 1 mg/kg, rat plasma LY344864 levels declined with time whereas b rain 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 stimulatio n of the trigeminal ganglion in rats. Taken together, these data demon strate that LY344864 is a selective 5-HT1F receptor agonist that can b e used to explore both the in vitro and in vivo functions of this rece ptor.