CONFORMATIONAL STUDIES OF (S)IDAZOXAN AND (S)METHOXYIDAZOXAN USING AM1-SEMIEMPIRICAL AND PM3-SEMIEMPIRICAL MOLECULAR-ORBITAL METHODS

Semiempirical calculations of the alpha-2 receptor antagonist, Idazoxan, its methoxy derivative, and their respective cations and anions revealed the most stable conformers were significantly affected by electrostatic interactions. These studies showed the importance of the intramolecular electrostatic interactions between the oxygen of the benzodioxane ring and the nitrogens of the imidazoline ring in determining the global minima of these molecules. The NH bond of the imidazoline ring was attracted to the dioxane oxygen and caused the imidazoline ring to rotate to a position allowing close proximity of these groups. Favorable interactions between the oxygens and the imidazoline stabilized the axial conformer, whereas unfavorable interactions increased the stability of the equatorial isomer. AM1 and PM3 calculations sometimes predicted different global minimum conformers, indicating the need for caution in reliance on either method, particularly when hydrogen bonds play an important role in determining the structure.