F. Durant

A reversible monoamine oxidase inhibitor, toloxatone : spectrophotometric and molecular orbital studies of the interaction with flavin adenine dinucleotide (FAD)

Abstract Toloxatone is a monoamine oxidase A (MAO A ) inhibitor, marketed as antidepressant devoid of the undesirable side effects of first-generation irreversible monoamine oxidase inhibitors (MAOIs). Its advantages arise from the reversible, competitive and specific nature of its inhibition. The mechanism for irreversible inhibition of MAO A at the molecular level is known (suicide substrate). A physicochemical study was undertaken to establish the mechanism of reversible inhibition by Toloxatone. After determination of structural and electronic properties [6], experimental and theoretical approaches were used to explore the possibility of a physical association between the eutomer R -Toloxatone and flavin, a cofactor of MAO A . For this, 2 models of flavin were used. First, the existence of a charge-transfer complex between R -Toloxatone and riboflavin was demonstrated by electron absorption spectroscopy. Second, ab initio Hartree-Fock calculations of frontier orbitals and electrostatic potentials confirm the favourable overlap of complementary electronic zones of R -Toloxatone and SCH 3 -lumiflavin for a defined relative orientation.

A reversible monoamine oxidase inhibitor, toloxatone: Structural and electronic properties

Abstract Toloxatone is a reversible MAOA-inhibitor, marketed as antidepressant (Humoryl®), with an original chemical structure. It differs from first generation irreversible MAOIs, known to induce covalent bonds with the enzyme active site. In order to understand the mechanism of the reversible inactivation of the MAO, as a first step, a detailed structural and electronic analysis was undertaken. An X-ray diffraction-crystallographic study showed that toloxatone is a planar molecule and brought to light hydrogen bonds and π-π interactions. MO calculations confirmed the planar structure as energetically favoured. Electronic analysis demonstrated a delocalization of both ring systems. The combined results give evidence for the potential of toloxatone to participate in reversible, long distance interactions with an appropriate partner.

Reversible inhibition of type B monoamine oxidase. Theoretical study of model diazo heterocylic compound

Summary Different families of heterocycles containing 2 to 4 nitrogen atoms (oxadiazolones, tetrazoles and oxadiazinone derivatives, so-called diazoheterocyclics) are currently used as lead compounds for the design of reversible and selective monoamine oxidase B (MAO-B) inhibitors. In order to clarify the mechanism of interaction of these molecules with the enzyme, we adopted a theoretical approach (ab initio calculations) and studied several structural and electronic properties of prototype molecules of the aryl diazo heterocyclic chemical series. This work provides a theoretical basis for structure-inhibition relationships in chemical series with potential IMAO-B properties.

A reversible monoamine oxidase inhibitor, Toloxatone: comparison of its physicochemical properties with those of other inhibitors including Brofaromine, Harmine, R40519 and Moclobemide

Summary Reversible, competitive and selective monoamine oxidase A inhibitors (MAO A Is) are an exciting new type of anti-depressants with a safe profile. The mechanism for reversible inhibition of MAO A at the molecular level is still unknown. The planar structure of most reversible MAO A Is and the well-defined acceptor power of flavin adenine dinucleotide (FAD), the cofactor of the enzyme, suggest that MAO A Is exert their inhibitory effect through charge-transfer interactions with the FAD. This hypothesis has been evaluated for Toloxatone 1 , the first reversible MAO A I marketed in France. In this work, we give evidence for the ability of other reversible MAO A Is, including Brofaromine 2 , Harmine 3 and R40519 4 to interact with the flavin cofactor in comparison with Moclobemide 5 , and we underline the physicochemical properties required for these interactions. First, the formation of a complex between each of the MAO A Is and riboflavin, a model of the flavin cofactor, is shown by electronic absorption spectroscopy. Essential electronic descriptors of MAO A Is, such as the molecular electrostatic potential and the topology of the frontier orbitals, are then calculated by the ab initio Hartree—Fock method and compared with those of previously studied Toloxatone. This confirms the electronic absorption spectroscopy results. Finally, the similarities between the different MAO A Is are underlined and an interaction model is discussed on the basis of a detailed analysis of the electronic descriptors of all the considered MAO A Is and the flavin nucleus.

Synthesis, pharmacology and X-ray studies of baclofen analogues

Baclofen (β-p-chlorophenyl-GABA) is the reference selective agonist for the bicuculline-insensitive GABAB receptor. The search for new compounds having a high affinity for the GABAB receptor is very important to clarify structural requirements. In that sense, we report the synthesis, binding studies and X-ray determinations of various 3-heteroaromatic γ-aminobutyric acids. Biochemical investigations concerning their abilities to displace [3H] muscimol (GABAA) and [3H] baclofen (GABAB) in binding studies showed that the 4-amino-3-(5-methoxybenzo[b]furan-2-yl)butanoic acid 6a (IC50 = 22.16 μM/R (−) [3H] baclofen; IC50 = 5.6 μM/RS [3H] baclofen) has a specific affinity for the GABAB receptor. The crystal structure of compounds 6a and 6b associated with computer graphics molecular superimpositions allows some structural requirements for GABAB receptor ligands to be proposed.

Characterization of the physico-chemical properties of the imidazopyridine derivative Alpidem. Comparison with Zolpidem

Abstract Zolpidem and Alpidem are 2 new imidazopyridine derivatives that represent a novel chemical and therapeutic class in the treatment of sleep and anxiety disorders, respectively. The former is a hypnotic agent and the latter behaves as an anxiolytic drug. In contrast to the benzodiazepines, both compounds act selectively at the ω1 (BZ1) but not at the ω2 (BZ2) modulatory sites of the GABAA supramolecular complex. The lack of affinity for ω2 (BZ2) modulatory sites may account for the absence of myorelaxant effects of these drugs. In order to determine the parameters that are important for the mode of interaction of these compounds with ω1 modulatory sites, their physico-chemical properties have been characterized and compared. Focus is directed on crystalline structures obtained from X-ray analysis, and electronic properties as electrostatic potential maps, atomic charges, delocalization effects, and electron densities obtained by ab initio molecular orbital calculations.

Experimental and theoretical study of reversible monoamine oxidase inhibitors: structural approach of the active site of the enzyme

Experimental and theoretical physico-chemical methods were used to investigate the interaction between aryl-oxazolidinones and monoamine oxidase (MAO). Several arguments suggest that these compounds interact with the flavin adenine dinucleotide (FAD) cofactor of MAO. The calculation using ab initio molecular orbital methods of the electronic properties of flavin and befloxatone, a reversible inhibitor of MAO A, led to a description of the interaction between aryl-oxazolidinones and the cofactor of the enzyme. Structure activity relationship results revealed additional sites of interaction with the protein core of MAO A. As a result of this work, a model is proposed for the reversible inhibition of MAO by oxazolidinones via long distance, reversible interactions with the FAD cofactor of the enzyme.

Structure analyses of R48455 a potent D2 antagonist and its inactive isomer R49399

Abstract In an attempt to identify the pharmacophore of D 2 -antagonists, the crystal structure of the potent D 2 -antagonist R48455 and its inactive geometrical isomer R49399 have been determined. Using PCILO calculations, it is shown that R48455 may adopt three low energy conformations with respect to rotation around the bond linking the cyclohexyl and the piperidine rings, whereas the inactive R49399 is rigidly locked in a single conformation corresponding to its crystal structure conformation. Employing the IFMFIT (interactive flexible molecular fitting) procedure, combined with X-ray data and PCILO results of tropapride and the title compounds, it is shown that the X-ray conformation of R48455 is most probably the biologically relevant one. Using the latter conformation as a template, a proposal is made as to the biologically relevant conformation of pimozide and spiperone.

Structural and electronic properties of anticonvulsant drugs: substituted 3-tertiary-amino-6-aryl-pyridazines, -1,2,4-triazines, and -pyrimidines

Crystal structures of three anticonvulsant compounds 1-[6-(4-chloro-2-methylphenyl)pyridazin-3-yl]piperidin-4-ol (1), 1-[6-(4-chlorophenyl)-1,2,4-triazin-3-yl]piperidin-4-ol (2), and 1-[5-(4-methoxyphenyl)pyrimidin-2-yl]piperidin-4-ol (3), have been solved by direct methods from single crystal X-ray diffraction data and refined by the full-matrix least-squares method. The X-ray diffraction results suggest a limited inclination of the phenyl ring, when ortho-substituted, with regard to the middle heterocycle, a marked delocalization of the piperidine nitrogen lone pair towards the middle heterocycle, and a critical orientation for the piperidine-like group due to this delocalization. Assumptions made on the basis of the experimental data are confirmed and quantified by ab initio molecular-orbital calculations.

Structure of an aminopyridazine derivative

Etude du bromure de (carboxy-3 propyl)-2 dihydro-2,3 phenyl-6 pyridaziniminium, C 14 H 16 N 3 O 2 + •Br − ; affinement jusqua R=0,040