title: Stereoselective actions of the isomers of metitepine at 5-HT1D receptors in the guinea pig brain.
abstract: The present studies examined the relative antagonist potencies of the optical isomers of the 5-HT receptor antagonist metitepine at the 5-HT1D binding site labelled by the novel radioligand serotonin-O-carboxymethylglycyl [125]iodotyrosinamide ([125I]GTI), and at the terminal 5-HT autoreceptor in guinea pig frontal cortex, a proposed model of 5-HT1D receptor activation. The pharmacological specificity of the [125I]GTI binding site in guinea pig frontal cortex was similar to previously published studies in the bovine cortical 5-HT1D recognition site labelled with [3H]5-HT. The (+) isomer of metitepine displaced [125I]GTI binding with a lower affinity (64 nM) than did the (-) isomer (18 nM), which was equiactive with the racemic mixture. The (-) isomer of metitepine was more effective than the (+) isomer at attenuating the inhibitory effects of 5-HT and sumatriptan at the guinea pig terminal 5-HT autoreceptor; the apparent pA2 of the (-) isomer was 8.0 (sumatriptan) and 7.7 (5-HT) while the apparent pA2 of the (+) isomer was 7.1 (sumatriptan) and 6.8 (5-HT). The (-) isomer was more effective than the (+) isomer at enhancing stimulated [3H]5-HT release. These findings support the identification of the guinea pig 5-HT terminal autoreceptor as a 5-HT1D receptor and reinforce the species homology between the 5-HT1B and 5-HT1D receptors.
authors: Merck, Sharp and Dohme Neuroscience Research Centre, Harlow, Essex, U.K.
authors: L O
authors: LO
authors: Wilkinson
authors: L M
authors: LM
authors: Hawkins
authors: M S
authors: MS
authors: Beer
authors: M F
authors: MF
authors: Hibert
authors: D N
authors: DN
authors: Middlemiss
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D002540:Cerebral Cortex / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D004151:Dipeptides; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D008297:Male; D008719:Methiothepin / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000031:analogs & derivatives / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D004151:Dipeptides; D007457:Iodine Radioisotopes; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C072128:serotonin-O-carboxymethyl-Gly-Tyr; D012701:Serotonin; D008719:Methiothepin; D011188:Potassium