STEREOSELECTIVE ACTIONS OF THE ISOMERS OF METITEPINE AT 5-HT1D RECEPTORS IN THE GUINEA-PIG BRAIN

The present studies examined the relative antagonist potencies of the optical isomers of the 5-HT receptor antagonist metitepine at the 5-HT(ID) binding site labelled by the novel radioligand serotonin-O-carboxymethylglycyl ([I-125]iodotyrosinamide ([I-125]GTI), and at the terminal 5-HT autoreceptor in guinea pig frontal cortex, a proposed model of 5-HT(ID) receptor activation. The pharmacological specificity of the [I-125]GTI binding site in guinea pig frontal cortex was similar to previously published studies in the bovine cortical 5-HT(ID) recognition site labelled with [H-3]5-HT. The (+) isomer of metitepine displaced [I-125]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 [H-3]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.