Synthesis and pharmacological evaluation of imidazoline sites I1 and I2 selective ligands

Several series of 2-aryl or heterocyclic-imidazoline compounds have been prepared and evaluated in vitro as imidazoline sites (I-1 and I-2) and alpha -adrenergic (alpha (1) and alpha (2)) receptor ligands. Their pK(i) values indicate that linkage of the imidazoline moiety at the 2-position with an aromatic substituent dramatically decreases alpha -adrenergic affinity. I-1 sites are more accessible by phenyl imidazolines substituted by a methyl or a methoxy group at the ortho or meta position. Indeed, 2-(2'-methoxyphenyl)-imidazoline (17) is one of the best I-1 ligands ever reported (pK(i) = 8.53 and I-1/I-2 > 3388). On the other hand, I-2 selectivity increases in the presence of a methyl group in the para position. The original compound, 2-(3'-fluoro-4'-tolyl)-imidazoline (31) is a new potent ligand for the I-2 sites with high selectivity (pK(i) = 8.53 and I-2/I-1 > 3388). (C) 2001 Elsevier Science Ltd. All rights reserved.