Monoamine Oxidase Inhibitors: Animal Pharmacology

Squires, Richard F.

doi:10.1007/978-1-4613-4045-4_1

Cited by 5 publications

(2 citation statements)

References 371 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Patients receiving M A 0 inhibitors are well known to be at risk for potentially lethal hypertensive and hyperthermic episodes (Murphy et al, 1984a,c), as well as various forms of behavioral toxicity such as hypomanic and psychotic episodes (Murphy, 1977). M A 0 inhibitor-treated patients also have essentially complete suppression of rapid eye movement (REM) sleep and changes in circadian neuroendocrine rhythms, including those for prolactin and melatonin (Squires, 1978;Cohen et al, 1982;Murphy et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

Marked Amine and Amine Metabolite Changes in Norrie Disease Patients with an X‐Chromosomal Deletion Affecting Monoamine Oxidase

Murphy

Sims

Karoum

et al. 1990

Journal of Neurochemistry

View full text Add to dashboard Cite

Urinary and plasma amines and amine metabolites were quantified in two individuals with Norrie disease resulting from a deletion in chromosomal region Xp11.3, recently reported to be associated with absence of the gene encoding monoamine oxidase (MAO)-A and nondetectable MAO-A activity in fibroblasts and MAO-B activity in platelets. Marked (four-to 100-fold) elevations in levels of urinary phenylethylamine, o-tyramine, and m-tyramine (which are preferential substrates for MAO-B) and marked reductions (90%) in levels of 3-methoxy-4-hydroxyphenylglycol (a deaminated metabolite of norepinephrine, a preferential substrate for MAO-A) in urine and plasma confirmed the presence of a systemic, functionally significant reduction in the activities of both MAO isozymes. The magnitude of these changes, which are equivalent to those found in subjects taking MAO-inhibiting antidepressants, suggests that early initiation of dietary and drug restrictions may be clinically important in these and other patients with X-chromosomal mutations involving MAO. These findings further support the proposition that the MAOA and MAOB genes are located in close proximity on the X chromosome. Negligible changes in the metabolites of dopamine and serotonin raise the possibility that other metabolic pathways are of importance for their production, that dietary or intestinal bacterial sources contribute substantially to the presence of these amine metabolites in urine, or both.

show abstract

Section: Discussionmentioning

confidence: 99%

Marked Amine and Amine Metabolite Changes in Norrie Disease Patients with an X‐Chromosomal Deletion Affecting Monoamine Oxidase

Murphy

Sims

Karoum

et al. 1990

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…MAO A and MAO B are mitochondrial flavoenzymes that play an important role in the oxidative deamination of several structurally diverse amines, including biogenic amines and xenobiotics (Singer, 1987;Squires, 1997;Strolin Benedetti and Tipton, 1998;Shih et al, 1999;Kalgutkar et al, 2001;Edmondson et al, 2004;Edmondson et al, 2009;Gaweska and Fitzpatrick, 2011). Both the enzymes catalyze the deamination reaction by cleavage of the C-H bond from the -carbon and reducing the flavin moiety (FAD to FADH 2 ) by transfer of a hydride equivalent from the amine (Supplementary Figure S1) (Kalgutkar et al, 2001;Edmondson et al, 2004;Edmondson et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Investigation into MAO B–Mediated Formation of CC112273, a Major Circulating Metabolite of Ozanimod, in Humans and Preclinical Species: Stereospecific Oxidative Deamination of (S)-Enantiomer of Indaneamine (RP101075) by MAO B

Bai

Shanmugasundaram

Selkirk

et al. 2021

Drug Metabolism and Disposition

View full text Add to dashboard Cite

Ozanimod, recently approved for treating relapsing MS, produced a disproportionate, active, MAO B-catalyzed metabolite (CC112273) that showed remarkable interspecies differences and led to challenges in safety testing. This study explored the kinetics of CC112273 formation from its precursor RP101075. Incubations with human liver mitochondrial fractions revealed K Mapp , V max and Cl int for CC112273 formation to be 4.8 M, 50.3 pmol/min/mg protein and 12 l/min/mg, respectively, while K M with human recombinant MAO B was 1.1 M. Studies with liver mitochondrial fractions from preclinical species led to K Mapp , V max and Cl int estimates of 3.0, 35 and 33 M, 80.6, 114, 37.3 pmol/min/mg and 27.2, 3.25 and 1.14 l/min/mg in monkey, rat and mouse, respectively, and revealed marked differences between rodents and primates, primarily attributable to differences in the K M . Comparison of Cl int estimates revealed monkey to be ~two-fold more efficient and the mouse and rat to be 11 and 4-fold less efficient than humans in CC112273 formation. The influence of stereochemistry on MAO B-mediated oxidation was also investigated using the R-isomer of RP101075 (RP101074). This showed marked selectivity towards catalysis of the S-isomer (RP101075) only. Docking into MAO B crystal structure suggested that even though both the isomers occupied its active site, only the orientation of RP101075 presented the C-H on the -carbon that was ideal for the C-H bond cleavage, which is a requisite for oxidative deamination. These studies explain the basis for the observed interspecies differences in the metabolism of ozanimod as well as the substrate stereospecificity for formation of CC112273.

show abstract

Monoamine Oxidase (MAO) Inhibitors in Psychiatric Therapy

Murphy¹

1989

Abnormal States of Brain and Mind

View full text Add to dashboard Cite

Monoamine Oxidase Inhibitors: Animal Pharmacology

Cited by 5 publications

References 371 publications

Marked Amine and Amine Metabolite Changes in Norrie Disease Patients with an X‐Chromosomal Deletion Affecting Monoamine Oxidase

Marked Amine and Amine Metabolite Changes in Norrie Disease Patients with an X‐Chromosomal Deletion Affecting Monoamine Oxidase

Investigation into MAO B–Mediated Formation of CC112273, a Major Circulating Metabolite of Ozanimod, in Humans and Preclinical Species: Stereospecific Oxidative Deamination of (S)-Enantiomer of Indaneamine (RP101075) by MAO B

Monoamine Oxidase (MAO) Inhibitors in Psychiatric Therapy

Contact Info

Product

Resources

About