Acido-basic properties of the catecholamine uptake inhibitors tetrabenazine and dihydrotetrabenazine.

Tetrabenazine (2-oxo-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7 hexahydro-11 bH-benzo (a) quinolizine) and dihydrotetrabenazine (2-hydroxy derivative) are inhibitors of catecholamine uptake by the chromaffin granules of adrenal medulla. In the 6.6 - 8.8 pH range, inhibition by tetrabenazine was pH-independent whereas dihydrotetrabenazine efficiency increased up to pH 8.3. The fluorescence and the buffer-octanol partition coefficient of these drugs was affected by the pH. Analysis of the pH-dependency of these effects indicated the existence of an acido-basic transition characterized by a pKa of 6.0 for tetrabenazine and 7.5 for dihydrotetrabenazine and associated with protonation of the tertiary amine of these molecules. For both compounds, the neutral form was less fluorescent and more soluble in octanol. Comparison of the uptake inhibition constants IC50 and of the neutralization curves showed that this form was the biologically active one. This result implies that the monoamine carrier of chromaffin granule membrane binds either to only deprotonated amines or to the molecules present only in the lipidic phase where the neutral form is largely predominant.