Evaluation of the antidepressant therapeutic potential of isocyanine and pseudoisocyanine analogues of the organic cation decynium-22

Antidepressant-like activity Herein we describe the synthesis and evaluation of antidepressant properties of seven analogues (1–7) of the low affinity/high capacity transporter blocker decynium-22 (D-22). All analogues (1–7) were synthesized via base promoted coupling reactions between N-alkylated-2-methylquinolinium iodides or N-alkylated-4-methylquinolinium iodides and electrophilic N-alkylated-2-iodoquinolinium iodides. All final compounds were purified by re-crystallization or preparative HPLC and initial evaluation studies included; 1) screening for in vitro α1-adrenoceptor activity (a property that can lead to unwanted side-effects), 2) measuring antidepressant-like activity in a mouse tail suspension test (TST), and 3) measuring effects upon mouse locomotion. The results showed some analogues have lower affinities at α1-adrenoceptors compared to D-22 and showed antidepressant-like activity without the need for co-administration of SSRIs. Additionally, many analogues did not affect mouse locomotion to the same extent as D-22. Plans for additional evaluations of these promising analogues, including measurement of antidepressant-like activity with co-administration of selective serotonin re-uptake inhibitors (SSRIs), are outlined. © 2017 Elsevier B.V.

Keywords

Antidepressants, Drugs, Cations, Iodides, Crystallization, Side effects, Dopamine

Citation

Krause-Heuer, A. M., Fraser-Spears, R., Dobrowolski, J. C., Ashford, M. E., Wyatt, N. A., Roberts, M. P., Gould, G. G. Cheah, W-C., Ng, C. K. L., Bhadbhade, M., Zhang, B., Greguric, I., Wheate, N. J., Kumar, N. Koek, W., Callaghan, P. D., Daws, L. C., & Fraser, B. H. (2017). Evaluation of the antidepressant therapeutic potential of isocyanine and pseudoisocyanine analogues of the organic cation decynium-22. European Journal of Medicinal Chemistry, 137, 476-487. doi:10.1016/j.ejmech.2017.06.011