Historic aspects in the identification of the I1 receptor and the pharmacology of imidazolines.

The central nervous system is involved in the control of arterial blood pressure. Stimulation of central alpha 2-adrenoceptors in the nucleus tractus solitarii (NTS) decreases sympathetic outflow, resulting in a fall in arterial blood pressure. One of the first antihypertensive substances with actions on the alpha 2-adrenoceptors of the NTS was alpha-methylnoradrenaline. Later on the imidazoline clonidine was developed for which numerous effects, mediated by alpha 2-adrenoceptors, in the CNS could be demonstrated. Since the centrally acting alpha 2-adrenoceptor agonists possess severe side effects, the development of more specific and selective centrally acting imidazolines resulted in the derivatives moxonidine and rilmenidine. The effects of the "second-generation imidazolines" could not be fully understood as alpha 2-adrenoceptor agonists. In the meantime, the rostral ventrolateral medulla (RVLM) has been identified as the site of action of the imidazolines and an I1-imidazoline binding site was characterized in this region. For the antihypertensive action of the imidazolines, agonism at the I1-imidazoline subtype seems to be responsible. In addition, an acid- and heat-stable endogenous substance, called clonidine displacing substance (CDS), was reported to bind at the putative I receptor. In 1992 a receptor protein for I receptors (70 kD) could be separated that is different from that of alpha 2-adrenoceptors. However, up to now we are still lacking the amino-acid sequence of the I receptor and its second messenger system.