Stereoselective actions of the isomers of metitepine at 5-HT1D receptors in the guinea pig brain

• Published in: Neuropharmacology Vol. 32; no. 3; pp. 205 - 208
• Main Authors: WILKINSON, L. O, HAWKINS, L. M, BEER, M. S, HIBERT, M. F, MIDDLEMISS, D. N
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 01.03.1993
• Subjects: Animals; Binding, Competitive - drug effects; Biological and medical sciences; Brain Chemistry - drug effects; Cerebral Cortex - anatomy & histology; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Dipeptides; Frontal Lobe - drug effects; Frontal Lobe - metabolism; Guinea Pigs; In Vitro Techniques; Iodine Radioisotopes; Male; Medical sciences; Methiothepin - pharmacology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Potassium - pharmacology; Receptors, Serotonin - drug effects; Serotonin - analogs & derivatives; Serotonin - metabolism; Serotonin Antagonists - pharmacology; Serotonin Receptor Agonists - pharmacology; Serotoninergic system; Stereoisomerism; Serotonin; Serotonin antagonist; Rodentia; Autoreceptor; In vitro; Biological activity; Stereoselectivity; Vertebrata; Biological fixation; Mammalia; Guinea pig; Animal; Neuromediator; Optical isomer
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/0028-3908(93)90101-8

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.