G. Evrard

A reversible monoamine oxidase A inhibitor, befloxatone: structural approach of its mechanism of action.

Experimental and theoretical physico-chemical methods were used to investigate the interaction between several reversible monoamine oxidase A inhibitors in the oxazolidinone series and the active site of the enzyme. Phenyloxazolidinones include toloxatone and analogues, among which befloxatone was selected as drug candidate for the treatment of depression. Identification of the forces responsible for the crystal cohesion of befloxatone reveals functional groups that could interact with monoamine oxidase. Calculation of electronic properties of those compounds using ab initio molecular orbital methods lead to a description of the mode of interaction between befloxatone and the cofactor of the enzyme. Electronic absorption spectroscopy measurements confirm the hypothesis of a privileged interaction of phenyloxazolidinone-type inhibitors with the flavin cofactor of MAO. Additional sites of interaction with the protein core of MAO A are also examined with regard to the primary structure of the enzyme. As a result of this work, a model is proposed for the reversible inhibition of MAO A by befloxatone via long distance, reversible interactions with the flavin adenine dinucleotide (FAD) cofactor of the enzyme and with specific amino acids of the active site. This model is partially corroborated by experimental evidence and should be helpful in designing new potent inhibitors of monoamine oxidase.

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.

STRUCTURAL REQUIREMENTS OF NON-PEPTIDE NEUROTENSIN RECEPTOR ANTAGONISTS

Neurotensin has a wide range of pharmacological effects in peripheral tissues and in the central nervous system. The crystal structures of two potent and selective neurotensin receptor antagonists, SR 48692 (I) and SR 48527 (II) have been determined and are reported in this work. By using computational calculations (semiempirical molecular orbital AM1) we studied the conformational properties of those compounds, including an inactive analogue SR 49711 (III) for comparison. Considering the pharmacological properties related to SR 48692 (I) and to optically synthetic analogues SR 48527 (II) and SR 49711 (III), we propose a model of bioactive conformation adopted by those neurotensin receptor antagonists.

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.

1-[[4-(Aminoalkoxy)phenyl]sulfonyl]indolizines: a novel class of calcium entry blockers. Relationships between chemical structure, stereoelectronic properties and anticalcic activity

The solid-state structures of a series of 1-[[4-(aminoalkoxy)phenyl]sulfonyl]indolizines have been determined by X-ray analysis. These molecules are known to be representative of a novel class of calcium entry blockers characterized by a new binding site associated with the L-type calcium channel. Previous 2-dimensional structure-activity relationship studies have shown that 1-sulfonylindolizines substituted in the 2 position by an isopropyl group and possessing an aralkylamine substructure were among the most potent calcium antagonists. A comparative study of the 3-dimensional X-ray structures and the electronic properties computed at the ab initio HF level of five 1-sulfonyl, 2-alkyl and 2-phenylindolizine calcium antagonists presenting different types of amine substructures indicates important similarities within the series. This has led us to propose the first pharmacophoric elements for this kind of compound.

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.

Stereochemical outcome of benzyllithiums synthesis from selenides

Abstract Epimerisation usually occurs during the synthesis of arylalcanes from the corresponding benzylselenides which involves benzyllithiums as intermediates. This has been used to produce stereoselectively arylcyclopentanes and arylcyclopropanes. γ-Benzenesulfonyloxyalkyl selenides substituted on the carbon bearing the benzenesulfonyl group behave differently and lead stereospecifically to arylcyclopropane derivatives.

Rhenium(V) and technetium(V) complexes with N-[2(1H-pyrolylmethyl)]-N'-(4-pentene-3-one-2)ethane 1,2-diaminate (C12H16N3O, MRP 20). X-ray crystal structures of H3MRP 20 and TcO(MRP 20)

Synthesis of N-[2(1H-pyrolylmethyl)]-N′-(4-pentene-3-one-2)ethane-1, 2-diamine has been effected and the compound characterised by X-ray diffraction. Crystal data for C12H19N3O: space group P21/c: a=10.358(3), b=7.953(1), c=15.640(4) A, β=101.63(1)°, V=1261(2) A3 to give Z=4 for D=1.165 g cm−3. Structure solution and refinement based on 2114 reflections converged at R=0.064, Rw=0.079. Reaction of this molecule with Bu4N[TcO(ethylene glycolate)2] results in the formation of a neutral technetium(V) complex [TcOL]. The X-ray structure of this complex confirms a five-coordinate, square based pyramidal geometry with no crystallographic axes of symmetry. Crystal data: orthorhombic space group P212121; a=11.701(1), b=14.949(2), c=7.516(1) A, V=1314.6 A3 to give Z=4 for D=1.68 g cm−3. Structure resolution and refinement based on 2115 reflections converged at R=0.037, Rw=0.033. Reaction of N-[2(1H-pyrolylmethyl)]-N′-(4-pentene-3-one-2)ethane-1,2-diamine with rhenium(V) oxotrichlorobistriphenylphosphine [ReOCl3(PPh3)2] or a rhenium(V) glycolato precursor yields the [ReOL] complex. The compounds have been studied by NMR, UVVis, IR spectroscopy as well as by mass spectrometry. The obtained results have been discussed in terms of the complex formation and the different transition metals.

Synthesis, structure and biological properties of Z-17α-(2-iodovinyl)-11β-chloromethyl estradiol-17β (Z-CMIV), a high affinity ligand for the characterization of estrogen receptor-positive tumors

Abstract Linkage of a 11β-chloromethyl group to estradiol-17β (E 2 ) dramatically increases the binding affinity of the steroid for the estrogen receptor (ER) with the formation of a quasi-irreversible steroid-receptor complex. We have synthesized the two isomers of 11β-chloromethyl-17α-iodovinyl-estradiol ( E -CMIV and Z -CMIV) by a novel route. Both derivatives demonstrated high binding affinity and selectivity for ER (RBAs: ER = 820 and 1008; SHBG = 1.2 and 0.25, respectively; E 2 = 100). On the basis of X-ray crystallographic data for Z -CMIV and its precursor, we have postulated that Z -CMIV might interact strongly with aromatic amino-acids within a hydrophobic groove of the ER hormone binding domain (HBD) that incorporates pockets corresponding to the 11β and 17α steroid substituents. The binding properties of Z -CMIV labeled with 125 I were investigated, especially its ability to detect and quantify altered ER forms with low binding affinity for E 2 . Sucrose density gradient analysis revealed that Z -CMIV has a higher activation potency than E 2 as it converts a higher proportion of non-activated monomers in the cytosol into activated monomers with the potential to dimerize. In in vitro (MCF-7 cells) and in vivo (rat uterus) determinations of estrogenic activity, Z -CMIV was as potent as E 2 in increasing progesterone receptor (PgR) concentrations and decreasing ER levels and in stimulating uterine growth. [ 125 I]- Z -CMIV could open the way to new applications in the diagnosis and therapy of ER-positive breast cancers, especially those containing altered (variant) ERs.