Hypotensive activity of serotonin antagonists; correlation with α1 -adrenoceptor and serotonin receptor blockade

For a series of 12 serotonin antagonists, largely varying in potency, the decrease in diastolic pressure was determined after intravenous injection into pentobarbitone-anaesthetized normotensive rats. The hypotensive activity of these antagonists was correlated with their affinity for α1 -adrenoceptors, established by (3H) prazosin radioligand displacement, and the 5-HT2 serotonergic receptor, determined by inhibition of specific (3H) mianserin binding. The radioligand binding assays were performed since they correspond to the in vivo antagonistic potencies of the antagonists at α1 - and 5-HT2 - receptors, respectively. A close correlation (r = 0.963) was found between the affinity for α1 -ad-renoceptors and hypotensive activity. On the other hand, a negative correlation of lower statistical quality (r = −0.808) existed between the affinity for 5-HT2 - receptors and the depressor potency. In this series of 12 compounds, the new antihypertensive drug ketanserin is included for which it has been speculated that it lowers blood pressure by virtue of its serotonin antagonistic activity. The results of the present study, however, point towards α1 -adrenolytic potency as an important mechanism in the hypotensive action of the drug.