Modulation of MAO activity by imidazoline and guanidine derivatives

I₂-binding sites (I₂-BS) are attributed to be a regulative site on monoamine oxidase (MAO). The in vivo and in vitro effects of various imidazoline and guanidine derivatives on MAO activity and on mitochondrial respiration were studied. Substances with high affinity for I₂-BS (antazoline, idazoxan, and cirazoline: IC₅₀ = 20.3, 33.8, and 43.4 μM) had a stronger inhibitory effect on MAO activity than did I₁-ligands (efaroxan, rilmenidine, clonidine, and moxonidine: IC₅₀ = 277, 801, 1224, and > 10,000 μM). Substances with the highest inhibitory effects were BDF8082 (IC₅₀ = 1.7 μM and 2-(2-benzofuranyl)-2-imidazoline (BFI; IC₅₀ = 4.0 μM). The enzyme is inhibited noncompetitively and is reversible, because its activity is completely or partially restored after dialysis. Agmatine, the putative endogenous ligand for IBS, also decreased MAO activity (IC₅₀ = 168 μM), whereas its precursor, L-arginine, and its metabolite, putrescine, had no effects. In vitro inhibition of MAO and mitochondrial respiration by the IBS-ligands tested could not be correlated, suggesting no link between the function of the inner and outer mitochondrial membrane. MAO activity in vitro was significantly reduced only by pargyline (-95%), BDF8082 (-68%), BFI (-43%), and 1-(m-chlorophenyl)-biguanide (-28%). Catecholamine content of livers obtained from animals treated with different IBS-ligands was consequently increased. In conclusion, the strong inhibitory effects of I₂ selective imidazoline ligands confirm the existence of I₂-BS as a regulatory site on MAO.