INHIBITION OF AMINE OXIDASE ACTIVITY BY DERIVATIVES THAT RECOGNIZE IMIDAZOLINE I-2 SITES

Nonadrenergic imidazoline binding sites (imidazoline I-2 sites) have b een described to be colocated with monoamine oxidase (MAO) in the mito chondrial fraction of various cell types. In the present work, the aut hors considered whether this colocation could be associated with a fun ctional interplay. in rat liver membranes, [H-3]-idazoxan binding to I -2 receptors was competed for by naphazoline and idazoxan, which also shared a high affinity for alpha-2 adrenoceptors (alpha-2 ARs). The ch emicals 2-n-heptylimidazoline (S 15430), 1-methyl-5-n-heptylimidazole (S 15674), 2-benzofuran-2-yl-imidazoline (RX 801077) and 2-(1,3-benzod ioxanyl)-2-imidazoline (RX 821029) exhibited higher affinity for I-2 r eceptors than for alpha-2 ARs. The most selective agent was S 15430 wi th a 150-fold higher affinity for liver I-2 receptors than for adipocy te alpha-2 ARs. Moreover, [H-3]-idazoxan binding was also competed for by several MAO inhibitors (MAOI) that are not imidazoline or guanidin ium derivatives such as tranylcypromine, harmaline, clorgiline and par gyline. Rat liver MAO activity was not only inhibited by MAOIs but als o by some imidazoline derivatives: cirazoline, naphazoline, S 15674, R X 801077 and RX 821029. Idazoxan had no effect on MAO activity; it nei ther inhibited MAO nor prevented the inhibition induced by other imida zolines or MAOIs. This suggested that the ligand recognition site of I -2 receptors was distinct from the MAOI target site. Furthermore, some imidazolines inhibited the activity of bovine plasma amine oxidase, a n enzyme that does not possess the same cofactor as MAO and is insensi tive to harmaline or pargyline. Taken together, these data indicate th at 1) some imidazolines, such as S 15430 or RX 801077, are more select ive for I-2 sites than idazoxan or cirazoline; 2) agents that recogniz e I-2 sites do not necessarily belong to the family of imidazoline or guanidinium derivatives; 3) the inhibition of amine oxidase activity r epresents a novel biological effect of I-2-site ligands, although it a ppears that the site of action of imidazolines involved in MAO inhibit ion may be distinct from that of classic MAOIs.