Binding of [3H]Ro 16-6491, a Reversible Inhibitor of Monoamine Oxidase Type B, to Human Brain Mitochondria and Platelet Membranes |
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Authors: | A M Cesura M D Galva R Imhof M Da Prada |
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Institution: | Department of Pharmacology, University of Milan, Italy;Pharmaceutical Research Department, F. Hoffmann-La Roche, Basel, Switzerland |
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Abstract: | The reversible inhibitor of monoamine oxidase type B (MAO-B) 3H]Ro 16-6491 binds specifically and with high affinity to a single population of binding sites in human frontal cortex crude mitochondria and platelet membranes. In both tissues binding equilibrium was reached after 1 h incubation at 20 degrees C. Dissociation of bound radioactivity was relatively fast at 20 degrees C (t1/2 = 90-120 min) whereas at 0 degrees C 3H]Ro 16-6491 showed the characteristics of a slowly dissociating ligand. Inhibitors and substrates of MAO-B inhibited binding of 3H]Ro 16-6491, whereas MAO-A blockers were much less potent. Ro 16-6491 was also a substrate for MAO-B and a stable unidentified intermediate of the oxidation of Ro 16-6491 possessing high affinity for the enzyme may account for the marked MAO-B inhibitory effect of the drug. According to this hypothesis Ro 16-6491 would behave as a mechanism-based reversible inhibitor. In conclusion, 3H]Ro 16-6491 binds selectively to MAO-B and represents an excellent new radioligand probe for studying the regional tissue distribution of this enzyme in normal and pathological conditions. |
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Keywords: | [3H]Ro 16-6491—High-affinity binding—Monoamine oxidase—Mechanism-based inhibition |
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