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

Abstract

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 α-adrenergic (α 1 and α 2) receptor ligands. Their p K i values indicate that linkage of the imidazoline moiety at the 2-position with an aromatic substituent dramatically decreases α-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 (p K 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 (p K i=8.53 and I 2/ I 1>3388).