PT  - JOURNAL ARTICLE
AU  - Rita Raddatz
AU  - Sandra L. Savic
AU  - Venkatesalu Bakthavachalam
AU  - John Lesnick
AU  - Jeffrey R. Jasper
AU  - Christopher R. McGrath
AU  - Angelo Parini
AU  - Stephen M. Lanier
TI  - Imidazoline-Binding Domains on Monoamine Oxidase B and Subpopulations of Enzyme
DP  - 2000 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1135--1145
VI  - 292
IP  - 3
4099  - http://jpet.aspetjournals.org/content/292/3/1135.short
4100  - http://jpet.aspetjournals.org/content/292/3/1135.full
SO  - J Pharmacol Exp Ther2000 Mar 01; 292
AB  - A series of phenoxy-substituted methylimidazoline derivatives were synthesized and used to define the ligand recognition properties of the imidazoline-binding domain (IBD) on monoamine oxidase (MAO)-B and its role in substrate processing. The rank order of potency for selected compounds in competitive binding studies with the imidazoline [3H]idazoxan was different from that in enzyme activity assays, suggesting that the IBD and the site involved in enzyme inhibition are distinct. IC50 values for inhibition of MAO-B activity by imidazoline/guanidinium ligands were one to two orders of magnitude greater than ligand concentrations that probably saturate the IBD, but were equal to theKd values of these ligands in competitive binding assays with the reversible MAO-B inhibitor [3H]Ro 19-6327. In addition, the degree of enzyme inhibition by these ligands was similar in platelet and liver, tissues exhibiting 10-fold differences in the amount of the IBD-accessible enzyme subpopulation. These data suggested that the inhibitory effect of these compounds on MAO-B activity involved a secondary interaction with the enzyme domain recognizing the inhibitor Ro 19-6327 and does not involve interaction with the IBD. Subsequent radioligand-binding studies indicated that human liver MAO-B actually existed as two distinct populations that differed in the accessibility of their IBD. The relatively small amounts of MAO-B possessing an accessible IBD (∼5% in human liver) precludes determination of the functional consequences of ligand binding to the IBD. This subpopulation of MAO-B may be selectively regulated or generated in different individuals or tissues and targeted by pharmacologically active compounds in a cell type-specific manner. The American Society for Pharmacology and Experimental Therapeutics