Cloning of MAO (monoamine oxidase) A and B has demonstrated unequivocally that these enzymes are made up of different polypeptides, and our understanding of MAO structure, regulation, and function has been significantly advanced by studies using their cDNA. MAO A and B genes are located on the X-chromosome (Xp11.23) and comprise 15 exons with identical intron-exon organization, which suggests that they are derived from the same ancestral gene. MAO A and B knock-out mice exhibit distinct differences in neurotransmitter metabolism and behavior. MAO A knock-out mice have elevated brain levels of serotonin, norephinephrine, and dopamine and manifest aggressive behavior similar to human males with a deletion of MAO A. In contrast, MAO B knock-out mice do not exhibit aggression and only levels of phenylethylamine are increased. Mice lacking MAO B are resistant to the Parkinsongenic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine. Both MAO A and B knock-out mice show increased reactivity to stress. These knock-out mice are valuable models for investigating the role of monoamines in psychoses and neurodegenerative and stress-related disorders.

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Monoamine oxidase: from genes to behavior.

Metal-organic frameworks (MOFs) are finding increasing application as solid catalysts for liquid phase reactions leading to the synthesis of fine chemicals. In the present review we have focused on those reports describing the use of MOFs as catalysts for the synthesis of N-containing heterocycles that is a class of organic compounds with high added value due to their therapeutic use as drugs and their remarkable biological activities. After an introduction describing relevant structural features of MOFs and the nature of their active sites, this manuscript is organized according to the type of N-containing heterocycle synthesized employing MOFs as catalysts including pyrimidines, N-substituted piperidines, quinolines, indoles, N-substituted imidazoles, triazoles and heterocyclic amides. Special attention has been paid to the structural stability of MOFs under the reaction conditions, to the occurrence of metal leaching and reusability. The final section of this review provides some concluding remarks and future prospects for the field, with emphasis on showing the superiority of MOFs with respect to other solid catalysts for this type of liquid phase organic reactions and pointing out that the final goal in this research would be the use of these materials as catalysts in real industrial synthesis.

Metal–organic frameworks as solid catalysts for the synthesis of nitrogen-containing heterocycles

Hydrogen isotopes are unique tools for identifying and understanding biological and chemical processes. Hydrogen isotope labelling allows for the traceless and direct incorporation of an additional mass or radioactive tag into an organic molecule with almost no changes in its chemical structure, physical properties, or biological activity. Using deuterium-labelled isotopologues to study the unique mass-spectrometric patterns generated from mixtures of biologically relevant molecules drastically simplifies analysis. Such methods are now providing unprecedented levels of insight in a wide and continuously growing range of applications in the life sciences and beyond. Tritium (3 H), in particular, has seen an increase in utilization, especially in pharmaceutical drug discovery. The efforts and costs associated with the synthesis of labelled compounds are more than compensated for by the enhanced molecular sensitivity during analysis and the high reliability of the data obtained. In this Review, advances in the application of hydrogen isotopes in the life sciences are described.

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Deuterium- and Tritium-Labelled Compounds: Applications in the Life Sciences

The presence of the so-called trace amines 2-phenylethylamine, m-tyramine, p-tyramine, m-octopamine, p-octopamine and tryptamine in the mammalian central nervous system has been known for several decades. Despite much initial interest, these amines have largely been thought of as little more than metabolic by-products. The recent description of a family of mammalian trace amine receptors has, however, seen a resurgence of interest in the physiological role of this class of compounds. Although the trace amines are well documented to cause amphetamine-like effects, such responses only occur at concentrations multiple orders of magnitude above normal physiological levels. As such, it seems unlikely that these responses reflect the true physiological role of the trace amines. In this article previous studies showing responses to physiologically relevant concentrations of trace amines are reviewed, along with those showing a reciprocal relationship between trace amine levels and fluctuations in basal monoaminergic tone. On the basis of these studies it is hypothesized that the trace amines function as endogenous neuromodulators of classical monoamine neurotransmitters. These effects are seen as an altered neuronal sensitivity to monoamine neurotransmitters, with no change in neuronal excitability in the absence of neurotransmitter.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1471-4159.2004.02501.x

Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators

Publisher Summary An enzyme inactivator, in general, is a compound that produces irreversible inhibition of the enzyme— that is, it irreversibly prevents the enzyme from catalyzing its reaction. Irreversible in this context, however, does not necessarily mean that the enzyme activity never returns only that the enzyme becomes dysfunctional for an extended (but unspecified) period of time. A mechanism-based enzyme inactivator, by the definition used here, is a compound that is transformed by the catalytic machinery of the enzyme into a species that acts as an affinity labeling agent, a transition state analog, or a tight-binding inhibitor (either covalent or noncovalent) prior to release from the enzyme. Mechanism-based enzyme inactivation is a powerful tool for the studies of enzyme mechanisms and mechanisms of enzyme inactivation, by small molecules. Mechanistic hypotheses can be tested by appropriate molecular design, utilizing the isotopically labeled analogs, to permit the elucidation of the structures of metabolites produced and to determine the portions of the mechanism-based inactivators that become covalently attached to the target enzyme. This approach to the studies of enzyme mechanisms is well suited for those who are geared more to the organic chemistry of enzymecatalyzed reactions and who have insights into the chemical machinery of active sites of enzymes. The use of mechanism-based enzyme inactivators is yet another of the very important methods in enzymology.

Mechanism-based enzyme inactivators.

A procedure for the quantitative evaluation of some amines present in mammalian tissues has been developed. It includes isolation of the amines by ion exchange chromatography followed by conversion to dansyl derivatives, chromatographic separation, and quantitation by the mass spectrometric integrated ion current technique. The use of an isotopically labelled internal standard improves the precision and sensitivity of the analysis.The concentrations of β-phenylethylamine in some tissues of male Wistar rats were (ng/g); brain 1.8 ± 0.4, heart 5.7 ± 3.1, kidney 20.5 ± 2.2, liver 2.0 ± 0.7, lung 4.0 ± 1.4, and spleen 4.7 ± 2.7. In the brain the hypothalamus contained 25.3 ± 5.0, the cerebellum 3.4 ± 0.5, the stem 2.2 ± 0.9, the caudate nucleus 8.0 ± 0.3, and the 'rest' 1.1 ± 0.2 ng/g, respectively.

Identification and distribution of beta-phenylethylamine in the rat.

A procedure for the quantitative evaluation of p-tyramine in mammalian tissues is described It involves isolation of the amine by ion-exchange chromatography, followed by conversion to the dansyl 

Identification and distribution of p-tyramine in the rat.

Two series of drugs, the aliphatic-N-methyl propargylamines and the aliphatic propargylamines, have been synthesised and shown to be specific, irreversible, and potent monoamine oxidase B inhibitors and neural rescue agents. In the latter case, an absolute stereochemical requirement for the R isomer exists. Both series of compounds have been shown, in numerous in vitro and in vivo experimental paradigms, to be effective neuronal rescue agents. Candidates from both series exhibit excellent bioavailability and pharmacokinetics and offer opportunities for treating neurodegenerative disorders and stroke and cognitive decline in companion animals. Drug Dev. Res. 42:150–156, 1997. © 1997 Wiley-Liss, Inc.

Aliphatic propargylamines: New antiapoptotic drugs

Stereospecific deuterium substitution at the α-carbon position of dopamine and its effect on oxidative deamination catalyzed by MAO-A and MAO-B from different tissues

David A. Durden

Papers

Identification and distribution of beta-phenylethylamine in the rat.

Identification and distribution of p-tyramine in the rat.

Aliphatic propargylamines: New antiapoptotic drugs

Stereospecific deuterium substitution at the α-carbon position of dopamine and its effect on oxidative deamination catalyzed by MAO-A and MAO-B from different tissues

Hydroxylation of β-phenylethylamine in the rat