Is imidazoline site a unique receptor? A correlation with clonidine-displacing substance activity

Many specific hypotensive drugs acting via the central alpha 2-adrenoceptors were designed based on their imidazoline/guanidine structure for use as antihypertensives. This unique structure, which is missing in the alpha 2-adrenoceptor natural ligands, led to the search for an endogenous, nonadrenergic ligand, and later on, for its putative receptor. Indeed, an endogenous ligand designated the "clonidine displacing substance" (CDS), was isolated and purified from bovine brain, and characterized in various cells. The most intriguing feature of CDS is its hypertensive action upon injection into the rostral ventrolateral medulla and its competition with clonidine. Is CDS a natural agonist which is displaced by clonidine or other hypotensive drugs? Does the unique imidazoline/guanidine structure imply a unique recognition site? Recent studies reported that an imidazoline site, distinct from the alpha 2-adrenoceptor, is abundant in many tissues, and it preferentially recognizes the imidazolino-guanidino type ligands. The physiological role of these sites is still not well defined. In the present study we show that the richest tissue in imidazoline sites is human placenta (1800 +/- 100 fmol/mg protein). The sites are distributed on the cell surface, as observed in studies of binding to intact cytotrophoblasts and cultured trophoblasts originating from human placenta. Binding studies show that the imidazoline site displays a unique pharmacological profile distinct from the alpha 2-adrenoceptor (eg, benzylidenamino-guanidine, Ki = 18.9 +/- 13.8 nmol/L for the imidazoline sites and Ki = 768 +/- 299 nmol/L for the alpha 2-adrenoceptors; guanidopyrol, Ki = 11.2 +/- 6.3 nmol/L for imidazoline sites and Ki = 10100 +/- 1515 nmol/L for the alpha 2-adrenoceptors).(ABSTRACT TRUNCATED AT 250 WORDS)