Conformational properties of butaclamol and isobutaclamol. Regularities in the structures of semirigid neuroleptics.

Conformational energy calculations have been performed on butaclamol and isobutaclamol using Allinger's MM2 (Molecular Mechanics II) program. Cis arrangements of rings D and E were found to be preferred by 1.4-1.9 kcal/mole for both compounds. Nevertheless, based on a molecular comparison with a number of semirigid neuroleptics, most notably loxapine and octoclothepin, it is suggested that trans arrangements are required for neuroleptic activity in the two compounds. However, trans conformer B of butaclamol, which was previously postulated as the biologically active form, was found to be 4.1 kcal/mole higher in energy, suggesting that it is less likely to play a significant pharmacological role. The biologically active forms are identified as trans conformer A for butaclamol and trans conformer B for isobutaclamol. Certain regularities in the structures of the semirigid neuroleptics are noted. It is also speculated that the cis conformers of protonated butaclamol may have unfavorable geometries for ion solvation, which would account for the anomalously low pKa measured for the compound. A similar explanation would also account for a trans conformer being found in the crystal structures of the bromide salts of butaclamol and dexaclamol.