3- and 5-Isoxazolol zwitterions: an ab initio molecular orbital study relating to GABA agonism and antagonism

Boulanger, Thierry; Vercauteren, Daniel P.; Durant, François; André, Jean‐Marie

doi:10.1016/s0022-5193(87)80144-3

Cited by 12 publications

(14 citation statements)

References 13 publications

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“…This situation is logical as the ammonium is not in presence of any other stabilizing molecular fragment, such as in crystals or close to the receptor. It has to be noted here that we also observed an intramolecular bond when we allowed total optimization of GABA within the s~o-3G basis set [7]. However, the optimized geometry was different; the carboxylate was stabilized by an hydrogen atom of the gamma-carbon atom.…”

Section: Mndo Geometry Optimization Of the Isolated Partnersmentioning

confidence: 64%

“…For isomuscimol, also classified as agonist, the bad electronic mimicry leads only to a drastic decrease in affinity. It was shown in our ab initio study [7] that the inversion of the nitrogen and oxygen atoms in the isoxazole ring, as compared to muscimol, has no effect on the side-chain orientation. Consequently, it was suggested that isomuscimol might still adopt an optimal conformation, as muscimol, to place the protonated function in front of the receptor and to activate this latter, thereby counterbalancing a bad interaction through the anionic head.…”

Section: Introductionmentioning

confidence: 61%

“…In a previous nonempirical molecular orbital study [7], we have demonstrated that the anionic site of the 3-isoxazolol compounds presents many electronic similarities with those of the GABA carboxyiate group. This is indicated by the finding of similar atomic charges and interatomic overlap populations suggesting a negative charge delocalized over three atomic centers.…”

Section: Introductionmentioning

confidence: 84%

“…In Table I, we report the affinity values for the GABA-A receptor expressed in IC,, (the lower IC,, the higher affinity) which indicate that the 3-isoxazolols are more potent, with an higher affinity for the GABA-A receptor, and an agonist character. We associate these characteristics to the fact that their electron structure better mimicks a carboxylate group, due to the presence of two identical negatively charged heteroatoms [7]. The compounds should bind themselves to the receptor through a bidentate interaction.…”

Section: Introductionmentioning

confidence: 99%

“…As our modeling philosophy is based on trying to help to the understanding of the interaction mechanism at a molecular level, a logical next step would be to consider a supermolecular approach, drug molecule-receptor fragment, in order to obtain relative results about the interaction energies. First, we want to be sure that the electronic similarities between the carboxylate moiety and the 3-isoxazolol anionic site, deduced from the charge population analyses [7] are not infirmed in the proposed interaction model. Moreover, the link through a bidentate interaction between a carboxylate or a 3-isoxazolol anionic site and a potential receptor fragment, an hypothesis formulated on isolated compounds considerations only, is not necessarily verified when considering a supermolecular model.…”

Section: Introductionmentioning

confidence: 99%

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3- and 5-Isoxazolol zwitterions: A model of interaction with the GABA-A receptor relating to agonism and antagonism

Boulanger

Vercauteren

Durant

et al. 1988

Int. J. Quantum Chem.

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Using molecular orbital methods, we propose various models of interactions between GABA or analogs (TACA, muscimol, isomuscimol) and an hypothetical receptor molecular fragment, a methylguanidinium ion. The respective geometries of the GABA-, TACA-, muscimol-, and isomuscimol-methylguanidinium ion complexes are optimized using the semi-empirical MNDO method. Stabilization energies of the complexes obtained by substraction of the heats of formation of the optimized complexes from those of the optimized isolated molecules differentiate the behavior of the anionic heads between the agonist and antagonist compounds. Affinity and stabilization are confmed by computing a6 initio sTo% ionization potentials and interaction energies taking into account counterpoise corrections. Results show a decrease of the interaction energy from GABA and TACA (-54.9 and -49.4 kcal/mol) to isomuscimol (-35.6 kcal/mol), via muscimol (-46.0 kcal/mol). The low interaction energy of the 5-isoxazolols as isomuscimol compared to the 3-isoxazolols, as muscimol, may explain their antagonist character.

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Section: Mndo Geometry Optimization Of the Isolated Partnersmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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3- and 5-Isoxazolol zwitterions: A model of interaction with the GABA-A receptor relating to agonism and antagonism

Boulanger

Vercauteren

Durant

et al. 1988

Int. J. Quantum Chem.

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Crystal Structure of R 29490, an N‐methylated Analog of a Potent Steroidic Gaba‐A Antagonist: 3α‐Hydroxy‐16‐Imino‐5β‐17‐Aza‐Androstan‐11‐One, R 5135

Boulanger

Vercauteren

Evrard

et al. 1991

Bulletin des Soc Chimique

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The synthesis of gornma-aminobutyric acid (GABA) receptor ligands is important in finding new therapeutic agerts and in helping to understand the mode of action of GABA. Amongst others, the steroid derivative 3a-hydroxy-16-imino-5pl7-aza-androstan-1 I-one, R 5135 ( Fig. la), was described as a potent GABA antagonist with an IC50 value of 0.02 pM to displace bound [3Hl GABA fiaa its A-receptor (bicuculline sensitive) (1).In order to increase the knowledge at the molecular level of the action mode of the steroid R 5135 (C1&gN2@) at the GABA-A receptor, we have studied its structural and electronic characteristics (21, as we did for other GABA-A ligands (3 -@. In order to confirm these properties, we have now solved by X-ray diffraction the crystal structure of R 29490 (C~~H~ON~@.HCI), a less active analog (Fig. lb). We report here the results. Fig. 1 : Planar suuctures of (a) R 5135 and (b) R 29490, C~~H~O N~@ . H C I , Mr = 354.64, crystals obtained from an ethyl acetate solution, crystal dimension = 0.18 xo.31 x0.10mm,monoclinic,~1,a= 10.364(1),b =7.784(2),c= 12.064(2)A,P=97.84(1) ', V=964.10A3, Z = 2, Dx = 1.22 g.cm-3, data collected on an Enraf-Nonius CAD-4 diffractometer, Mo Ka (M.71073 A), 1 = 1.72 cm-1, F (Ooa) = 386.9 range = 1-25 ' , 2169 independent reflections (-12ShS12; -5SkS9; 011S14). final R = 0.042 for 1507 observed reflections (I 2 2.5 a(I)), max. and min. heights in final A-Fourier = 0.38 and -0.35 e.A-3, noabsorption corrections made. The structure was solved using the SHELX86 program u) and refined with the SHEW76

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DFT and Ab initio computational study on the reactivity sites of the GABA and its agonists, such as CACA, TACA, DABA, and muscimol: In the gas phase and dielectric media

Serdaroğlu

2010

Int J of Quantum Chemistry

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The reactive behavior of GABA and its agonist molecules have been investigated using B3LYP hybrid density functional method at the 6-311þþG** basis set level, in the gas phase and dielectric media. The calculations have been performed to obtain optimized geometries, relative energies, net atomic charges, HOMO, and LUMO energies. Solvent effects have been analyzed using isodensity polarized continuum model (IPCM) for four different solvents, which are chloroform, ethanol, DMSO, and H 2 O. The results have suggested that both the amino group and carboxyl group have been two of the most important active site for interactions between all compounds and their receptors. In addition they have suggested that the amino group reflects the difference in biological activity for each all molecules. The structures of these agonists have provided an essential foundation for subsequent structure-activity analysis of ligand binding at GABA receptors, neuronal uptake inhibitors and transporters.

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3- and 5-Isoxazolol zwitterions: an ab initio molecular orbital study relating to GABA agonism and antagonism

Cited by 12 publications

References 13 publications

3- and 5-Isoxazolol zwitterions: A model of interaction with the GABA-A receptor relating to agonism and antagonism

3- and 5-Isoxazolol zwitterions: A model of interaction with the GABA-A receptor relating to agonism and antagonism

Crystal Structure of R 29490, an N‐methylated Analog of a Potent Steroidic Gaba‐A Antagonist: 3α‐Hydroxy‐16‐Imino‐5β‐17‐Aza‐Androstan‐11‐One, R 5135

DFT and Ab initio computational study on the reactivity sites of the GABA and its agonists, such as CACA, TACA, DABA, and muscimol: In the gas phase and dielectric media

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