A COMPARISON OF THE PHYSICOCHEMICAL AND BIOLOGICAL PROPERTIES OF MIRTAZAPINE AND MIANSERIN

Although the chemical structures of the antidepressants mirtazapine an d mianserin are closely related there are considerable differences in their biological properties. To find an explanation of this, various p hysicochemical properties of mirtazapine and mianserin were measured o r calculated. Isosteric replacement of CH in mianserin by N in mirtaza pine has profound effects on physicochemical properties. The charge di stributions as indicated by NMR and calculated by semi-empirical quant um mechanics differ, not only for the changed aromatic A-ring (as expe cted), but also in other regions of the molecule. The N5 atom in parti cular, which is conjugated to the changed aromatic ring, is less negat ively charged in mirtazapine than in mianserin. Consequently the oxida tion potential of mirtazapine is significantly higher than that of mia nserin. Another result of this difference in charge distribution is th at the (calculated) dipole-moment vectors of the compounds are oriente d roughly perpendicular to each other. The dipole moment of mirtazapin e is, moreover, three times larger than that of mianserin; mirtazapine is, therefore, more polar than mianserin and this is reflected in a l ower retention index. Finally, the basicity of mirtazapine, expressed as the pK(a) value, is slightly but significantly lower than that of m ianserin. The observed differences between the physicochemical propert ies of mirtazapine and mianserin result in different interactions of t hese two antidepressants with macromolecules, such as receptors, trans porters and metabolizing enzymes; this might explain the differences o bserved in pharmacological activity and metabolic and kinetic behaviou r, that is, the reduced affinity for the alpha(1)-adrenoceptor and neg ligible noradrenaline reuptake of mirtazapine compared with mianserin.