title: Cloning and characterization of the guinea pig 5-HT1F receptor subtype: a comparison of the pharmacological profile to the human species homolog.
abstract: The anti-migraine compound, sumatriptan, has been shown to have substantial affinity for the cloned human 5-HT1F receptor suggesting that, in addition to 5-HT1B/5-HT1D receptor subtypes, the 5-HT1F receptor may be a therapeutic target for the treatment of migraine. Several investigators have used the guinea pig plasma extravasation model to evaluate potential anti-migraine drugs. Since species differences in the pharmacology of serotonin receptors are well known, we compared the pharmacological profiles of the cloned human and guinea pig 5-HT1F receptors in order to validate the usefulness of the in vivo model in predicting anti-migraine activity of compounds targeted for humans. We have cloned the guinea pig 5-HT1F by homology to the human 5-HT1F receptor and evaluated its pharmacological profile using radioligand binding assays. The cloned guinea pig 5-HT1F gene exhibited 94% amino acid identity to the corresponding human homolog. High affinity (Kd approximately 10 nM) [3H]5-HT binding was detected to membranes obtained from Cos-7 cells transiently expressing the guinea pig 5-HT1F receptor. The cloned guinea pig receptor displayed typical 5-HT1F receptor pharmacology with 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 (r2 = 0.72, slope = 0.76) observed between the binding affinities of compounds for these two species homologs. In situ hybridization studies in guinea pig tissue revealed 5-HT1F receptor mRNA expression in the neurons 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 development of neurogenic inflammation. Dorsal root ganglion cells also moderately expressed the 5-HT1F transcripts. The localization of the 5-HT1F receptor to areas involved in the mediation and transfer of nociceptive information implies a role for this receptor in pain processing. These findings indicate that a selective 5-HT1F agonist may be a novel approach to treat migraine.
authors.affiliation: Synaptic Pharmaceutical Corporation, Paramus, NJ 07652, USA.
authors.forename: N
authors.initials: N
authors.lastname: Adham
authors.forename: J A
authors.initials: JA
authors.lastname: Bard
authors.forename: J M
authors.initials: JM
authors.lastname: Zgombick
authors.forename: M M
authors.initials: MM
authors.lastname: Durkin
authors.forename: S
authors.initials: S
authors.lastname: Kucharewicz
authors.forename: R L
authors.initials: RL
authors.lastname: Weinshank
authors.forename: T A
authors.initials: TA
authors.lastname: Branchek
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D016678:Genome; D006168:Guinea Pigs; D000882:Haplorhini; D006801:Humans; D017403:In Situ Hybridization; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis; D011869:Radioligand Assay; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D011985:Receptors, Serotonin