Sonia Collin

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.

QSAR of nortropane-substituted benzamides: use of lipophilic (RP-HPLC) and electronic (1H NMR) parameters

Abstract The pharmacological and biochemical activities of 4-benzamido-nortropanes, a subgroup of neuroleptic drugs, are correlated with experimental and calculated parameters describing structural properties, such as lipophilicity or electronic distribution. The lipophilicity was experimentally measured using the HPLC method and theoretically calculated using hydrophobic Π values. 1H NMR chemical shifts were used to describe the electronic structure. In a series of fifteen tropapride analogues with various substituents at position 5 on the benzamide moiety, a parabolic relationship was obtained between hydrophobic values and anti-dopaminergic activities, indicating that lipophilicity is certainly the major property influencing their affinity for the D2 receptor. The linear correlation between affinities and the amidic hydrogen chemical shifts in a series of eight 3-substituted derivatives shows that the stability of the intrabenzamidic hydrogen bond may play a preponderant role in some cases. The electronic properties of some substituted orthopramides are quantified by ab initio theoretical calculations in order to explain the indirect effect of the substituent at position 3.

Structural requirements of Na+-dependent antidopaminergic agents: Tropapride, Piquindone, Zetidoline, and Metoclopramide Comparison with Na+-independent ligands

SummaryMolecular graphic design coupled with PCILO and crystallographic results have been used to investigate the three-dimensional structure of Tropapride, Piquindone, Zetidoline, and Metoclopramide, four dopamine D-2 receptor antagonists showing Na+-dependent binding. Three putative pharmacophoric elements, a nitrogen lone pair, a phenyl ring and a carbonyl moiety, are similarly oriented in all the Na+-dependent drugs. Conversely, for Na+-independent analogs, the two latter pharmacophoric elements play a subordinate role, but two Π-electron regions are systematically localized on the other side of the molecule: the first is a phenyl group while the second is a carbonyl function as in butyrophenones, a cyano group as in R48455, or a phenyl ring as in diphenylbutylpiperidines or tricyclics. The presence of a benzyl ring on this side in Tropapride might explain its weak extrapyramidal effects.

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.

Crystal and molecular structure analysis of benzamide neuroleptics and analogs (VIII):endo- andexo-2,3-dimethoxy-N-[8-(phenylmethyl)-8-azabicyclo[3.2.1]oct-2-y1]-benzamide hydrochloride: C23H28N2O3·HCl

The crystal structures ofendo- andexo-2,3-dimethoxy-N-[8(phenylmethyl)-8-azabicyclo[3.2.1]oct-2-y1]benzamide hydrochloride have been determined by single-crystal X-ray diffraction techniques, and refined by full-matrix least squares. The endo-compound crystallizes in the monoclinic space groupP21/n witha=12.389(2) Å,b=22.861(3) Å,c=8.019(2) Å,β=93.58(2)°, andZ=4; the exo-compound crystallizes in the monoclinic space groupP21/a witha=26.295(12) Å,b=12.503(4) Å,c=6.667(7) Å,β=97.80(6)°, andZ=4. The calculated densities are 1.22 and 1.27 g cm−3 respectively. FinalR-factors are 0.04 for the endo and 0.05 for the exo-compound. Comparison with a very active analog, the tropapride, suggests that the lack of antipsychotic activity is due to a different orientation of the dimethoxyphenyl or carbonyl group for the exo- and endo-compound, respectively.

Contribution of crystal structures, molecular electrostatic potential maps and lipophilicity data to structure-activity relationships of some conformationally restricted nortropane benzamide neuroleptics

Structural, electronic, and lipophilicity characteristics of dihydro-2,3-methoxy-4 and dihydro-2,3[(phenylmethyl)-8 aza-8 bicyclo[3.2.1.] octyl-3]-2 1H-isoindolone-1, (exo), two conformationally restricted nortropane benzamide derivatives (subgroup of neuroleptic drugs) have been determined and compared to other more “flexible” analogs in order to explain their pharmacological antidopaminergic D2 activities. Molecular structures of both compounds were obtained using single crystal X-ray crystallography; molecular electrostatic potential maps were computed at theab initio MO STO-3G level, and the capacity factors were measured by RP-HPLC.

Stereoelectronic requirements of benzamide 5HT3 antagonists. Comparison with D2 antidopaminergic analogues

Renzapride (I) and Tropapride (IV) are very similar substituted benzamides but are distinguishable by their pharmacological profile: the former is a potent 5HT(3) antagonist while the latter is a very active D-2 antidopaminergic drug. A combination of experimental methods (X-ray diffraction and H-1 NMR spectroscopy) and theoretical calculations (semiempirical molecular orbital AM1) were used to investigate the conformational space of three 5HT(3) antagonists: Renzapride (I, BRL24924), DAU6215 (II) and Ondansetron (III, GR38032). The analysis of their solid state conformations as well as their isolated state structures allows us to propose a 5HT(3) pharmacophoric model which is compared to the one previously reported for benzamide D-2 antagonists, represented by Tropapride (IV).

Molecular structure analysis of benzamide neuroleptics. Part 13. A tropapride sulphonamidic analogue C15H22N3O3SCl

The crystal structure of the title compound (1) has been solved by direct methods from single crystal X-ray diffraction. Monoclinic, space group P21/c with a= 9.277(1), b= 9.977(2), c= 18.557(2)A, β= 98.44(1)°; Z= 4. The final R-factor is 0.03 for 2 923 observed reflections. The inactive title compound (for the dopaminergic D2 receptor) containing a benzosulphonamide function is compared with a very potent benzamide analogue: tropapride (2). The molecular conformation of the title compound obtained by optimal superimposition (flexible fitting) of the proposed pharmacophoric elements with those of tropapride corresponds to a significantly less stable conformation as shown by ab initio LCAO-MO-SCF calculations. In fact, the electron-attracting mesomeric effect of the, sulphone group excludes the formation of a strong intramolecular hydrogen bond which would stabilize the tropapride-like conformation of the lateral chain.