Design, synthesis and evaluation of 1-(1,5-bis(4-substituted phenyl)-2-methyl-1 H -pyrrol-3-yl)- N -methylmethanamines as SERT inhibitors with potential antidepressant action.
Anjani Uma Rani WunnavaSony Priya KuratiKilari Eswar KumarMurali Krishna Kumar MuthyalaPublished in: RSC medicinal chemistry (2022)
BM212 is a potent anti-TB agent with pharmacophoric features similar to the antidepressant drug sertraline. The shape-based virtual screening of the DrugBank database on BM212 resulted in the identification of several CNS drugs with appreciable Tanimoto scores. The docking simulations also ascertained the selectivity of BM212 towards the serotonin reuptake transporter protein (SERT) with a docking score of -6.51 kcal mol -1 . Based on the SAR data available for sertraline and other antidepressant drugs, we designed, synthesized and screened twelve 1-(1,5-bis(4-substituted phenyl)-2-methyl-1 H -pyrrol-3-yl)- N -methylmethanamines (SA-1 to SA-12) for in vitro SERT inhibition and in vivo antidepressant activity. The compounds were screened for in vitro 5HT reuptake inhibition using the platelet model. Among the screened compounds, (1-(1,5-bis(4-chlorophenyl)-2-methyl-1 H -pyrrol-3-yl)- N -methylmethanamine) showed the same serotonin uptake inhibition (absorbance 0.22) as that of the standard drug sertraline (absorbance 0.22). BM212 had an effect on 5-HT uptake, albeit a weaker one compared to the standard (absorbance 0.671). Further, SA-5 was screened for in vivo antidepressant activity using the unpredictable chronic mild stress (UCMS) protocol to induce depression in mice. The effect of BM212 and SA-5 on the behaviour of the animals was assessed and compared against the standard drug sertraline. SA-5 at 20 mg per kg body weight was found to have a statistically significant impact on the behaviour of depressed animals.
Keyphrases
- major depressive disorder
- body weight
- molecular dynamics
- protein protein
- bipolar disorder
- ionic liquid
- adverse drug
- drug induced
- molecular dynamics simulations
- randomized controlled trial
- molecular docking
- mycobacterium tuberculosis
- small molecule
- stress induced
- emergency department
- electronic health record
- blood brain barrier
- adipose tissue
- metabolic syndrome
- artificial intelligence
- physical activity
- sleep quality
- binding protein
- deep learning
- wild type
- high fat diet induced
- data analysis
- monte carlo