Differential selectivities of RU 24969 and 8-OH-DPAT for the purported 5-HT1A and 5-HT1B binding sites. Correlation between 5-HT1A affinity and hypotensive activity

Abstract RU 24969 and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) inhibited the specific binding of [ 3 H]5-HT (2 nM) to rat brain membranes with shallow displacement curves. The displacement data were best fitted with a model of two independent, high and low affinity binding sites. Following addition of spiperone (1 μM) as a selective ligand for the putative 5-HT 1A recognition site of [ 3 H]5-HT, the displacement curve of RU 24969 underwent a leftward shift, whereas spiperone induced a shift to the right for the displacement curve of 8-OH-DPAT. In contrast to spiperone, pindolol (1 μM) shifted the displacement curve of RU 24969 to the right. These results suggest that RU 24969 possesses preference for the purported 5-HT 1B subtype of central 5-HT 1 recognition site. The reported significant linear correlation between hypotensive activity following intravenous (i.v.) administration to anesthetized rats and affinity for the central 5-HT 1 binding site could only be maintained by incorporation of the affinity of RU 24969 for its low and 8-OH-DPAT for its high affinity binding site. Based on the proposal that the 5-HT 1A site corresponds to the high affinity site of 8-OH-DPAT and the low affinity site of RU 24969, it is hypothesized that the late depressor phase of 5-HT agonists in rats is mediated by activation of peripheral (vascular) 5-HT receptors which have similarities with the 5-HT 1A subtype of central 5-HT 1 recognition site.