HISTORIC ASPECTS IN THE IDENTIFICATION OF THE I-1 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 I-1-imidazoline binding site was characterized in this region. For the antihypertensive action of the imidazolines, agonism at the I-1-imidazoline subtype seems to be responsible. In addition, an acid- and heatstable 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.