Imidazoline receptors: Qualitative structure-activity relationships and discovery of tracizoline and benazoline. Two ligands with high affinity and unprecedented selectivity

Rational Design of the New Antihypertensive I1-Receptor Ligand 2-(2- Biphenyl-2-yl-1-methyl-ethyl)-4,5-dihydro-1H-imidazole

“…that the phenyl group in the ortho position of the aromatic ring of biphenyline (2), interacting with some residues of the aromatic cluster of TM6 [21], triggered the receptor activation; therefore, also the agonist properties of 4 might be ascribed to the interaction of the ortho phenyl group with a similar aromatic cluster of the I 1 -Rs. However, since in previous studies we observed that isosteric replacement of the oxygen atom of the bridge with a methylene group greatly reduced the interaction with α 2 -ARs [18,22], we can hypothesize that the aminoacid sequence of the receptor protein, interacting with this portion of ligand, may represent a site of selectivity for the two receptor systems. In fact, polar interactions in such an area appear favorable for both systems but, as outlined in Table 1, they play a critical role in the case of the α 2 -ARs [pK i α 2 of compound (2) >> pK i α 2 of compound (4), and pK i α 2 of compound (1) > pK i α 2 of compound (3)]; non polar interactions appear to be effective only in the case of the I 1 -Rs.…”

Respective contributions of α‐adrenergic and non‐adrenergic mechanisms in the hypotensive effect of imidazoline‐like drugs

“…Radioligand binding assays S23515, as rilmenidine, is an aminooxazoline compound and S23757 is an imidazoline close to benazoline and idazoxan (Figure 1) (Pigini et al, 1997). They were highly selective for I 1 BS over a 1 -and a 2 ARs (Table 1).…”

“…I 2 -binding sites Rabbit kidney membranes preparation and a nities of drugs were performed as described (Pigini et al, 1997) except that 2-BFI (10 mM) was used to de®ne nonspeci®c binding instead of cirazoline (10 mM). a 1 -and a 2 -adrenoceptors binding assays Calf frontal cortex membranes were prepared as described (Van Liefde et al, 1993) for binding assays to a 1 -and a 2 ARs.…”

Radiosynthesis of a 2‐substituted 4,5‐dihydro‐1H‐[2‐11C] imidazole: the I2 imidazoline receptor ligand [11C] benazoline

“…It has a high affinity for the imidazoline I 2 receptor ðpK i ¼ 9:07Þ with a high selectivity for I 2 relative to the a 1 -and the a 2 receptors (2691-and 18621-fold, respectively). 2 Our interest in the study of receptor systems in the living human brain by positron emission tomography (PET) prompted us to envisage labelling of compound 1 with the short-lived positron-emitting radioisotope carbon-11 (half-life = 20.4 min). To date, no suitable PET ligand has been available for the imidazoline receptor system.…”