Identification and Characterization of a New Serotonergic Recognition Site with High Affinity for 5‐Carboxamidotryptamine in Mammalian Brain

We analyzed the existence of an additional serotonin (5‐HT) receptor subtype, sensitive to 5‐carboxamidotryptamine, in the mammalian brain. Radioligand binding studies with [ 3 H]5‐HT were carried out in rat, guinea pig, and human brain membranes, in the presence of unlabeled drugs to mask the binding to all known 5‐HT receptors, with the exception of 5‐HT 1E sites. Under these conditions, unlabeled 5‐carboxamidotryptamine still showed a biphasic competition curve with a nanomolar affinity component. Saturation studies with 5‐[ 3 H]carboxamidotryptamine were carried out in the presence of (±)‐8‐hydroxy‐2‐(di‐ n ‐propylamino)tetralin, mesulergine, and ergotamine, to mask the binding to all receptors known to be labeled by 5‐carboxamidotryptamine. These studies showed the existence in cortex and hippocampus from guinea pig and human brain of a remaining binding site with high affinity ( pK D = 7.8–8.1) and a unique pharmacological profile. 5‐HT and 5‐carboxamidotryptamine showed nanomolar affinity, whereas 5‐methoxytryptamine recognized this binding site with intermediate affinity. Other drugs exhibited low or very low potency in inhibiting this binding. The addition of 5′‐guanylylimidodiphosphate significantly reduced the number of binding sites labeled by 5‐[ 3 H]carboxamidotryptamine, in the presence of the masking drugs described above, indicating the interaction with a GTP‐binding protein. Preliminary autoradiographic studies in human brain appear to indicate that this 5‐HT binding site is present in areas such as the globus pallidus, neocortex, and hippocampus, among others.