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Focus on Moclobemide REVIEW PAPERS Biochemistry and Pharmacology of Reversible Inhibitors of MAO-A Agents: Focus on Moclobemide N.P.V. Nair, M.D., S.K. Ahmed, M.D., N.M.K. Ng Ying Kin, Ph.D. Douglas Hospital Research Centre, Verdun, Quebec Submitted: December 21, 1992 Accepted: August 10, 1993 Moclobemide, p-chloro-N-[morpholinoethyl]benzamide, is a prototype of RIMA (reversible inhibitor of MAO-A) agents. The compound possesses antidepressant efficacy that is comparable to that of tricyclic and polycyclic antidepressants. In humans, moclobemide is rapidly absorbed after a single oral administration and maximum concentration in plasma is reached within an hour. It is moderately to markedly bound to plasma proteins. MAO-A inhibition rises to 80% within two hours; the duration of MAO inhibition is usually between eight and ten hours. The activity of MAO is completely reestablished within 24 hours of the last dose, so that a quick switch to another antidepressant can be safely undertaken if clinical circumstances demand. RIMAs are potent inhibitors ofMAO-A in the brain; they increase the free cytosolic concentrations ofnorepinephrine, serotonin and dopamine in neuronal cells and in synaptic vesicles. Extracellular concentrations of these monoamines also increase. In the case of moclobemide, increase in the level of serotonin is the most pronounced. Moclobemide administration also leads to increased monoamine receptor stimu- lation, reversal of reserpine induced behavioral effects, selective depression of REM sleep, down regulation of 3-adrenoceptors and increases in plasma prolactin and growth hormone levels. It reduces scopolamine-induced performance decrement and alcohol induced performance deficit which suggest a neuroprotective role. Tyramine potentiation with moclobemide and most other RIMA agents is negligeable. Key Words: monoamine oxidase, reversible inhibitors, moclobemide INTRODUCTION The therapeutic efficacy ofcurrently available antidepres- plicated in the pathophysiology of affective disorders. It is sants is well established despite gaps in our understanding of believed that a deficit in biogenic amine transmission results the neurochemical pathology and pathogenesis of mood in depressive illness (Leonard 1989). The monoamine defi- disorders. Central monoaminergic neurotransmitters, partic- ciency hypothesis is based mostly on extrapolations from ularly 5-hydroxytryptamine (5-HT) (Heninger et al 1984) profound depression observed after treatment with reserpine The action of was are im- (Pletscher 1991). mood-altering reserpine and norepinephrine (Schildkraut 1965), consistently attributed to the depletion of brain vesicular stores of mono- aminergic neurotransmitters. The acute pharmacological ac- Address reprint requests to: N.P.V. Nair, M.D., Director, tion of tricyclic antidepressants (TCAs) and monoamine Douglas Hospital Research Centre, 6875 LaSalle Boulevard, Ver- oxidase inhibitors (MAOIs) also supports the monoamine dun, Quebec, Canada H4H 1R3. deficiency hypothesis (Schildkraut 1965; Langer and J Psychiatr Neurosci, Vol. 18, No. 5, 1993 214 November 1993 Reversible inhibitors ofMAO-As 215 Schoemaker 1988). In vitro studies showed that TCAs are ing of these amines at diverse receptor sites. Electro- physi- potent blockers of nerve terminal 5-HT and norepinephrine ological, behavioral and binding studies have shown that reuptake (Richelson 1984; Richelson and Pfenning 1984). long-term administration enhances al adrenoceptor sensitiv- The compounds thereby retard inactivation and prolong the ity and reduces pre-synaptic cX2-adrenergic, B-adrenergic and synaptic life of monoamines; the availability of neurotrans- 5-HT2 receptor sensitivity (Sugrue 1983; Menkes et al 1983; mitters at the post-synaptic site is therefore increased. Mason and Angel 1983). The implication ofthese alterations MAOIs, in contrast, decrease the pre-synaptic intracellular in receptor sensitivity in relation to the etiology ofdepression metabolism of neurotransmitters and therefore can increase and the response to treatment needs to be clarified further. the availability of amines to be released into the extracellular However, taking into consideration the time-lag between the space. The overall effect is an enhancement of functional initiation of treatment and the onset of therapeutic actions, neurotransmission involving the parent amines. With a few the chronic effects ofantidepressants on post-synaptic recep- exceptions, the development of new generation antidepres- tors appears to be more relevant to the mechanism of antide- sants has largely been the result ofminor modifications in the pressant action. molecular structures of the established antidepressants This review will focus on the biochemistry and pharma- (Richelson 1984). cology of a new class of monoamine oxidase inhibitors, the The acute pharmacological effect of antidepressant med- reversible inhibitors of MAO-A (RIMAs). Compared with ications is consistent with the amine hypothesis of the etiol- the TCAs, these compounds have more specific pharmaco- ogy and pathogenesis of depression. There is also logical properties, in that they act primarily on specific accumulating evidence that alterations of neurotransmitter intraneuronal isoenzymes located in the pre-synaptic regions. function, especially that of5-HT, are related to the pathogen- Monoamine oxidase (MAO) is the enzyme which metab- esis ofdepression and the therapeutic response to antidepres- olizes different types of biogenic amines, including 5-HT, sant medications (van Praag et al 1987). However, the norepinephrine and dopamine by oxidative deamination clinical effects of these drugs, specifically their time-course (Fig. 1). It is found in two catalytically distinguishable forms, of action, for example, the time-lag, are not consistent with MAO-A and MAO-B, which are encoded by two different their proposed mechanisms of action (Oswald et al 1972). genes (Bach et al 1988). The isoenzymes A and B have Pre-clinical and clinical studies have demonstrated several distinct differences in their primary structure as well as in changes caused by the long-term administration of antide- their main human organ sources, subcellular localization, pressants (Charney et al 1981; Blier et al 1990). Thus, in tissue distribution and substrate preference (Fowler and addition to their known roles as re-uptake inhibitors of bio- Tipton 1984; Denney and Denney 1985). Both isoenzymes genic amines, TCAs can directly interact and alter the bind- have the redox co-enzyme flavin adenine dinucleotide cova- MAO St Fl' I It (11 1), N I 1) I 0) I IP ____ __, t CI1IO NllI, -1- 11202 SlI'Ell 2 (I) Aldchlydc rc(Ilictase > Rt-C1201l ()-cAc 10 - (l)) A\ldcliy(lc (Icliydrogciiase __ __ ~~~~~~~~>1t-CCO21 1 N E, 5-1 IT I)A 1,2 a 1I,2l, 1,2 b I1,2 DI IP', MilP' 5-IIIAA IIVA, DOP'AC Fig. 1. Catabolism ofmonoamines. NE = noradrenaline; 5-HT = serotonin; DA = dopamine; DHPG, 3,4-dihydroxyphenylglycol; MHPG, 3-methoxy-4-hydroxyphenylglycol; 5-HIAA = 5-hydroxyindoleacetic acid; HVA = homovanillic acid; DOPAC = 3,4-dihydroxyphenylacetic acid. The formation ofHVA and MxHPG involves an additional enzyme, catechol 0 methyl transferase (COMT). 216 Journal ofPsychiatry & Neuroscience VoL 18., No. S., 1993 Fig. 2. Chemical structures ofRIMA agents. lently bound by a thioether bond to a cysteine moiety. The Benedetti and Dostert 1987), the status of MAOIs in the enzymes are usually presenton the outermitochondrial mem- treatment of depression deserves re-evaluation. Compounds brane of both neuronal and non-neuronal cells (Greenwalt which selectively inhibit MAO-A and MAO-B have been 1972). Most human tissues contain both types of MAO. In developed (Delini-Stula et al 1988). Specific MAO-B inhib- the periphery, MAO-A is found mostly in the sympathetic itors, such as deprenyl, are being used with some success to terminals, intestinal mucosa and placenta, whereas MAO-B treat degenerative diseases, such as Parkinson's disease predominates in the liver, lungs and bloodplatelets (DaPrada (Parkinson Study Group 1989a; 1989b; Teravainen 1990), et al 1988; Youdim et al 1980). In the human brain, mRNA but have a very limited use for treating depression (Mann et for MAO-A occurs in the cell bodies of noradrenergic neu- al 1989). However, selective inhibitors ofMAO-A are found rones in the locus ceruleus, and mRNA for MAO-B is present to have antidepressant efficacy with less risk of fatal side- in serotonergic cell bodies in the raphe nuclei (Richards et al effects, such as hypertensive crisis. Moclobemide, brofarom- 1992). MAO-A is responsible for the oxidative deamination ine, toloxatone, cimoxatone and Ro 41-1049 are among those of 5-HT, norepinephrine and epinephrine, respectively, in compounds which selectively and reversibly inhibit MAO-A decreasing order of substrate preference for the enzyme, (Da Prada et al 1990). Together, they form a new class of whereas MAO-B preferentially deaminates benzylamine and antidepressants, the reversible inhibitors of MAO-A. the trace amine 2-phenylethylamine (Knoll and Magyar Clorgyline also selectively inhibits MAO-A, but only irre- 1972). Dopamine and tyramine are common substrates for versibly. both types of MAO (Strolin Benedetti and Dostert 1987). It is therefore apparent that MAO-A is the enzyme primarily Biochemistry responsible for the alteration of monoaminergic functions hypothetically related to the etiopathogenesis ofmood disor- Chemically, the reversible MAO-A inhibitors are deriva- ders and should thus be the target isoenzyme in determining
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