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.