A novel dual serotonin transporter and M-channel inhibitor D01 for antidepression and cognitive improvement

Cognitive dysfunction is a core symptom common in psychiatric disorders including depression that is primarily managed by antidepressants lacking efficacy in improving cognition. In this study, we report a novel dual serotonin transporter and voltage -gated potassium Kv7/KCNQ/M-channel inhibitor D 01 (a 2-methyl-3-aryloxy-3-heteroarylpropylamines derivative) that exhibits both anti -depression effects and improvements in cognition. D01 inhibits serotonin transporters (Ki = 30.1 +/- 6.9 nmol/L) and M channels (IC50 = 10.1 +/- 2.4 mmol/L). D01 also reduces the immobility duration in the mouse FST and TST assays in a dose -dependent manner without a stimulatory effect on locomotion. Intragastric administrations of D01 (20 and 40 mg/kg) can significantly shorten the immobility time in a mouse model of chronic restraint stress (CRS) -induced depression -like behavior. Additionally, D01 dose -dependently improves the cognitive deficit induced by CRS in Morris water maze test and increases the exploration time with novel objects in normal or scopolamine -induced cognitive deficits in mice, but not fluoxetine. Furthermore, D01 reverses the long-term potentiation (LTP) inhibition induced by scopolamine. Taken together, our findings demonstrate that D01, a dual -target serotonin reuptake and M channel inhibitor, is highly effective in the treatment-resistant depression and cognitivedeficits, thus holding potential for development as therapy of depression with cognitive deficits. 2024 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Instituteof Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/)