Imidazoline-binding domains on monoamine oxidase B and subpopulations of enzyme.
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 [(3)H]idazoxan was different from that in enzyme activity assays, suggesting that the IBD and the site involved in enzyme inhibition are distinct. IC(50) 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 the K(d) values of these ligands in competitive binding assays with the reversible MAO-B inhibitor [(3)H]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 ( approximately 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.
Raddatz
R
R
Department of Pharmacology, Medical University of South Carolina, Charleston, South Carolina, USA.
Savic
S L
SL
Bakthavachalam
V
V
Lesnick
J
J
Jasper
J R
JR
McGrath
C R
CR
Parini
A
A
Lanier
S M
SM
D001665:Binding Sites; D006801:Humans; D019329:Idazoxan / Q000378:metabolism; D007093:Imidazoles / Q000378:metabolism*; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000378:metabolism*; D010848:Picolinic Acids / Q000378:metabolism
D007093:Imidazoles; D008996:Monoamine Oxidase Inhibitors; D010848:Picolinic Acids; C059303:lazabemide; D008995:Monoamine Oxidase; D019329:Idazoxan