Project 170982

Inhibiting the monoamine oxidase B (MAO-B) enzyme in the human brain enhances availability of several neurotransmitters and neuromodulators. As a result, MAO-B inhibition is effective in slowing the progression of Parkinson's disease, and may help people having difficulty in stopping smoking. The potential health benefits to Canadians of a drug which inhibits MAO-B, without affecting other related enzymes, are therefore substantial. However, the only drug available works well in the laboratory, but loses selectivity in patients, while a recent clinical trial of a novel drug with improved properties failed because of toxicity issues. Designing a new MAO-B inhibitor requires that we understand how MAO-B works, and how it differs from closely related enzymes. With such knowledge, we can exploit these differences in mechanism and structure to design new potent and selective drugs. Our CIHR-funded research has generated significant new data that allow us to understand some of the most critical differences between MAO-B and related enzymes. Our current application proposes to use a variety of techniques to expand upon our preliminary observations and fully characterise two novel sites on the MAO-B protein. We propose that these sites represent novel targets for future inhibitors that will form a new class of antiParkinsonian and smoking cessation therapies.

using a combination of techniques to characterize novel binding sites on MAO-B for the development of new selective inhibitors