I1 imidazoline receptors involved in cardiovascular regulation -: Where are we and where are we going?

Clonidine-like drugs (hybrid drugs) reduce blood pressure by acting centrally at both alpha(2)-adrenergic receptors (alpha(2)AR) and I-1 receptors (I1R). Some attempts at cloning I1R have failed,probably because of the lack of selectivity of the ligands. Recently, compounds acting exclusively at I1R were synthesized: LNP 911, LNP509, and S23515. For example, LNP911 has a K-d value of 1.7 nmol/L at I1R. LNP509 and S23515 reduce blood pressure when injected centrally in anesthetized animals, whereas S23757 behaves as an antagonist of hypotensive imidazolines. LNP509 reduces blood pressure even in genetically engineered mice lacking functional alpha(2)AR. An exclusive action at central I1R is therefore sufficient to modify blood pressure. With the help of drugs selective for I1R and alpha-methylnoradrenaline, selective for alpha(2)AR, we showed that imidazoline and alpha(2)-adrenergic mechanisms interact synergistically in controlling the blood pressure. Such a synergism may explain the very powerful hypotensive effects of hybrid drugs. The new ligands selective for I1R will be very helpful to investigate the molecular features and the signaling system of I1R.