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.
Boulanger
T
T
Laboratoire de Chimie Moléculaire Structurale, Facultés Universitaires Notre-Dame de La Paix, Namur, Belgium.
Vercauteren
D P
DP
Durant
F
F
Andre
J M
JM
D055598:Chemical Phenomena; D002621:Chemistry; D003437:Crotonates / Q000494:pharmacology; D018756:GABA Antagonists; D007555:Isoxazoles / Q000494:pharmacology; D008968:Molecular Conformation; D009118:Muscimol / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000378:metabolism
D003437:Crotonates; D018756:GABA Antagonists; D007555:Isoxazoles; D011725:Pyridines; D011963:Receptors, GABA-A; C055331:4-aminocrotonic acid; C055333:isomuscimol; D009118:Muscimol; C038164:5,6,7,8-tetrahydro-4H-isoxazolo(4,5-d)azepin-3-ol; C041650:isothaz; C055334:iso THIP; C015542:gaboxadol