A comparison of the physicochemical and biological properties of mirtazapine and mianserin.
Although the chemical structures of the antidepressants mirtazapine and mianserin are closely related there are considerable differences in their biological properties. To find an explanation of this, various physicochemical properties of mirtazapine and mianserin were measured or calculated. Isosteric replacement of CH in mianserin by N in mirtazapine has profound effects on physicochemical properties. The charge distributions as indicated by NMR and calculated by semi-empirical quantum mechanics differ, not only for the changed aromatic A-ring (as expected), but also in other regions of the molecule. The N5 atom in particular, which is conjugated to the changed aromatic ring, is less negatively charged in mirtazapine than in mianserin. Consequently the oxidation potential of mirtazapine is significantly higher than that of mianserin. Another result of this difference in charge distribution is that the (calculated) dipole-moment vectors of the compounds are oriented roughly perpendicular to each other. The dipole moment of mirtazapine is, moreover, three times larger than that of mianserin; mirtazapine is, therefore, more polar than mianserin and this is reflected in a lower retention index. Finally, the basicity of mirtazapine, expressed as the pKa value, is slightly but significantly lower than that of mianserin. The observed differences between the physicochemical properties of mirtazapine and mianserin result in different interactions of these two antidepressants with macromolecules, such as receptors, transporters and metabolizing enzymes; this might explain the differences observed in pharmacological activity and metabolic and kinetic behaviour, that is, the reduced affinity for the alpha 1-adrenoceptor and negligible noradrenaline reuptake of mirtazapine compared with mianserin.
Kelder
J
J
NV Organon, Oss, The Netherlands.
Funke
C
C
De Boer
T
T
Delbressine
L
L
Leysen
D
D
Nickolson
V
V
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D004563:Electrochemistry; D005243:Feces / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D000078785:Mirtazapine; D008956:Models, Chemical; D009638:Norepinephrine / Q000378:metabolism; D010084:Oxidation-Reduction; D011789:Quantum Theory; D011869:Radioligand Assay; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000378:metabolism
D000929:Antidepressive Agents, Tricyclic; D018340:Receptors, Adrenergic, alpha-1; D008803:Mianserin; D012701:Serotonin; D000078785:Mirtazapine; D009638:Norepinephrine