CLONING AND CHARACTERIZATION OF THE GUINEA-PIG 5-HT1F RECEPTOR SUBTYPE - A COMPARISON OF THE PHARMACOLOGICAL PROFILE TO THE HUMAN SPECIES HOMOLOG

The anti-migraine compound, sumatriptan, has been shown to have substa ntial affinity for the cloned human 5-HT1F receptor suggesting that, i n addition to 5-HT1B/ 5-HT1D receptor subtypes, the 5-HT1F receptor ma y be a therapeutic target for the treatment of migraine. Several inves tigators have used the guinea pig plasma extravasation model to evalua te potential anti-migraine drugs. Since species differences in the pha rmacology of serotonin receptors are well known, we compared the pharm acological profiles of the cloned human and guinea pig 5-HT1F receptor s in order to validate the usefulness of the in vivo model in predicti ng anti-migraine activity of compounds targeted for humans. We have cl oned the guinea pig 5-HT1F by homology to the human 5-HT1F receptor an d evaluated its pharmacological profile using radioligand binding assa ys. The cloned guinea pig 5-HT1F gene exhibited 94% amino acid identit y to the corresponding human homolog. High affinity (K-d similar to 10 nM) [H-3]5-HT binding was detected to membranes obtained from Cos-7 c ells transiently expressing the guinea pig 5-HT1F receptor. The cloned guinea pig receptor displayed typical 5-HT1F receptor pharmacology wi th the following rank order of binding affinities: 5-HT > sumatriptan > 1-NP = DHE > alpha-methyl 5-HT > metergoline > methiothepin > 5-CT. The pharmacological profiles of the cloned guinea pig and human 5-HT1F receptors were very similar as reflected by the high correlation (r(2 ) = 0.72, slope = 0.76) observed between the binding affinities of com pounds for these two species homologs. In situ hybridization studies i n guinea pig tissue revealed 5-HT1F receptor mRNA expression in the ne urons of the trigeminal ganglion, suggesting that the 5-HT1F receptor may play a role in the presynaptic inhibition of neuropeptide release at the level of the intracranial vasculature, thereby blocking the dev elopment of neurogenic inflammation. Dorsal root ganglion cells also m oderately expressed the 5-HT1F transcripts. The localization of the 5- HT1F receptor to areas involved in the mediation and transfer of nocic eptive information implies a role for this receptor in pain processing . These findings indicate that a selective 5-HT1F agonist may be a nov el approach to treat migraine. (C) 1997 Elsevier Science Ltd.