Thierry Boulanger

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.

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

The Hartree-Fock ab initio molecular orbital method has been applied to eight compounds: GABA (gamma-amino butyric acid) (1), its partially rigidified analog, TACA (trans-4-aminocrotonic acid) (2), six isoxazolol analogs; muscimol (5-aminomethylisoxazol-3-ol (3), THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) (4), THAZ (5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol) (5), isomuscimol (3-aminomethylisoxazol-5-ol) (6), iso-THIP (4,5,6,7-tetrahydroisoxazolo[3,4-c] pyridin-5-ol) (7), and iso-THAZ (5,6,7,8-tetrahydro-4H-isoxazolo[3,4-d]azepin-5-ol) (8). GABA is an endogenous inhibitory transmitter. The four following molecules (2), (3), (4) and (5) are agonist: they bind themselves to the GABA receptors and induce approximately the same effect as GABA. (6) is lightly agonist, presenting a lower affinity. Compounds (7) and (8) are antagonists, giving rise to convulsion. Optimized molecular conformations of GABA (1), muscimol (3) and isomuscimol (6) are discussed. Geometric and electronic parameters showing the presence of intramolecular hydrogen bonds are presented. The permutation of the heteroatoms in the isoxazole ring has no effect on the side-chain orientation explaining maybe the agonist character of isomuscimol, being able to adopt easily and exactly the active conformation. Atomic charge distributions and electronic overlap populations for all compounds have been computed in order to try to understand why their GABAergic activities can be so different. The computed values show that the 3-isoxazolol ring mimics in a good way the carboxylic function of GABA. They also illustrate the larger electronic delocalization within the 5-isoxazolol ring and therefore the resulting antagonist character, except for isomuscimol.

Crystal structure and quantum electronic analyses of pitrazepin, a γ-aminobutyric acid (GABA) receptor antagonist

The crystal structure of pitrazepin has been solved by direct methods from single-crystal X-ray diffraction data and refined by full-matrix least squares: monoclinic, space group P21/c, a= 18.845(2), b= 15.424(5), c= 16.950(4)A, β= 104.51(2)°, Z= 4, two pitrazepin and three water molecules per asymmetric unit, final R factor is 0.042. This compound binds with high affinity to pharmacological GABA-A receptors; it acts as an antagonist. Ab initio molecular orbital calculations for pitrazepin and GABA show that the piperazine and triazole rings of pitrazepin might be considered as the GABA-mimetic moieties.

Comparison between optimized and crystal structures of R5135, a potent steroidic GABA-A antagonist: ab initio molecular orbital charge population analysis

Abstract The molecular structure of hydroxy-3α imino-16 5β-aza-17 androstanone-11, R5135, a potent steroidic GABA-A antagonist, has been optimized using the semi-empirical MNDO method. Its crystal structure has been solved by X-ray diffraction. Theoretical and experimental structural results are compared. Using both geometries, ab initio MO calculations have been applied within the STO-3G basis set to quantify the electronic structure. The results of the Mulliken charge population analysis show a good agreement between the computed atomic charges and interatomic overlap populations for both structures. These values are finally compared with those reported earlier for GABA.

Molecular structure and electronic populations of two ligands for the benzodiazepine receptor sites: 3-methyl-6-phenyl- and 3-methyl-7-phenyl-1,2,4-triazolo[4,3-b]pyridazines, SR95199 and SR95195; x-ray diffraction analysis andab initio MO calculations

Abstract(I) 3-methyl-6-phenyl-1, 2, 4-triazolo[4,3-b]pyridazine, SR95199, C12H10N4,Mr=210.2, monoclinic,P21/n,Dx=1.36 g cm−3,

X-ray crystal structures of three nonbenzodiazepinic ligands for the benzodiazepine receptor sites: SR95926, CMW1842, and L16317:nab initio MO study of the electronic properties

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Structure and molecular modeling of GABAA receptor antagonists

, =1.54178 Å,F(000)=440,T=293 K, finalR=0.049, (II) 3-methyl-7-phenyl-1, 2, 4-triazolo[4,3-b]pyridazine, SR95195, C12H10N4,Mr=210.2, monoclinic,P21/n,Dx=1.37 g cm−3, Cu