Some pharmacological and clinical aspects of reversible MAO inhibitors

Interactions of monoamine oxidase with substrates and inhibitors

“…Review articles, partly or totally devoted to reversible MAOIs, have already been published, 42,192,199,200,216 and the reader can refer particularly to refs. 42 and 192 for information on the different chemical structures of reversible MAOIs.…”

Mechanism of monoamine oxidase‐A inhibition by BW 1370U87

“…In fact, BW 1370U87 is unique among M A 0 inhibitors in that it contains no nitrogen. Its selectivity for MAO-A, reversibility , and competitive mechanism of inhibition are a combination of properties that would be expected to allow maximum protection against an accumulation of tyramine in peripheral tissues such as liver [Strolin Benedetti, 1984;White et al, 19861. Although the affinity of BW 1370U87 for MAO-A appears to be at least 5,000 times that of tyramine (ratio of KJK,), the reversible and competitive mechanism of MAO-A inhibition by BW 1370U87 will ensure that tyramine, at sufficiently high levels, can displace the inhibitor from MAO-A active sites.…”

“…In fact, BW 1370U87 is unique among M A 0 inhibitors in that it contains no nitrogen. Its selectivity for MAO-A, reversibility , and competitive mechanism of inhibition are a combination of properties that would be expected to allow maximum protection against an accumulation of tyramine in peripheral tissues such as liver [Strolin Benedetti, 1984;White et al, 19861. Although the affinity of BW 1370U87 for MAO-A appears to be at least 5,000 times that of tyramine (ratio of KJK,), the reversible and competitive mechanism of MAO-A inhibition by BW 1370U87 will ensure that tyramine, at sufficiently high levels, can displace the inhibitor from MAO-A active sites. This is because inhibition by a simple competitive inhibitor will depend on relative concentrations of inhibitor and substrate, as well as their affinities for the enzyme [Webb, 19631. The mechanism of MAO-A inhibition by BW 137OU87 appears distinctly different from those observed with brofaromine or moclobemide, two other selective MAO-A inhibitors.…”

“…During recent years there has been renewed interest in the development of MA0 inhibitors with improved safety profiles for use in depressive illnesses, largely because of two important advances in M A 0 research: (1) the discovery that MA0 exists as two distinct enzyme types, A and B [reviewed by Denney and Denney, 1985;Bach et al, 1988;Lan et al, 19891 and (2) the evidence that inhibition of only the A form is sufficient to produce an antidepressant action in animal models and in humans [Wheatley, 1970;Christmas et al, 1972;Lipper et al, 1979;Murphy et al, 19811. Because tyramine can be metabolized at both MAO-A and -B sites, it is reasonable to think that a selective MAO-A inhibitor would allow at least partial metabolism of dietary tyramine. An additional advantage may be gained if the inhibition mechanism is also reversible and competitive with tyramine, so that a high concentration of this amine can successfully compete with the inhibitor at peripheral MAO-A sites [Strolin Benedetti, 1984;White et al, 19861. An MAO-A inhibitor with this type of selective, competitive mechanism could have broad application, not only in depression, including geriatric depression, but also in a variety of other illnesses for which traditional irreversible MA0 inhibitors may be considered too risky [Zisook, 1985;Nies, 19841. This report describes the actions of BW 1370U87 (1-ethylphenoxathiin 10,lO-dioxide; Fig.…”