Abstract
SMe1EC2M3 is a pyridoindole derivative related to the neuroleptic drug carbidine. Based on the structural similarities of SMe1EC2M3 and known serotonin (5-HT), norepinephrine, and dopamine reuptake inhibitors, we hypothesized that this compound may also have triple reuptake inhibition efficacy and an antidepressant-like effect. PreADMET and Dragon software was used for in silico prediction of pharmacokinetics and pharmacodynamics of SMe1EC2M3. Forced swim test was used to evaluate its antidepressant-like effects. Extracellular in vivo electrophysiology was used to assess 5-HT, norepinephrine, and dopamine reuptake inhibition efficacy of SMe1EC2M3. PreADMET predicted reasonable intestinal absorption, plasma protein binding, and blood-brain permeability for SMe1EC2M3. Dragon forecasted its efficiency as an antidepressant. Using behavioral measurements, it was found that SMe1EC2M3 decreased immobility time and increase swimming time during the forced swim test (FST). Electrophysiological investigations showed that SMe1EC2M3 dose-dependently suppressed the excitability of 5-HT neurons of the dorsal raphe nucleus (DRN), norepinephrine neurons of the locus coeruleus (LC), and dopamine neurons of the ventral tegmental area (VTA). The SMe1EC2M3-induced suppression of 5-HT, norepinephrine, and dopamine neurons was reversed by the antagonists of serotonin-1A (5-HT1A; WAY100135), α-2 adrenergic (α2, yohimbine), and dopamine-2 receptors (D2, haloperidol), respectively. We conclude that SMe1EC2M3 is prospective triple 5-HT, norepinephrine, and dopamine reuptake inhibitor with antidepressant-like properties, however future studies should be performed to complete the pharmacological profiling of this compound.
Highlights
Major depression is considered the most severe mental disorder and one of the most severe medical conditions in general, in terms of cost, prevalence, disability, and mortality rate [1]
In our study we focused on SMe1EC2M3 ((±)-cis ethyl 8-methoxy-6-methyl-3,4,4a,5,9bHhexahydro-1H-pyrido[4,3-b]indole-2-carboxylate (Figure 1)
The partition and distribution coefficients speak for a good bioavailability
Summary
Major depression is considered the most severe mental disorder and one of the most severe medical conditions in general, in terms of cost, prevalence, disability, and mortality rate [1]. The etiology of depression is not yet completely understood, it is well established that serotonin (5-HT), norepinephrine and dopamine systems play a key role in the treatment of this disorder [2]. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) have been used as first-choice drugs for the treatment of depression, indicating the key role of 5-HT neurotransmission in pharmacotherapy of depression. The remission of the symptoms happens only in 30–40% of the patients after the treatment with a first-choice SSRI [3]. Even if patients meet remission criteria, at least one symptom remains unresolved in almost all patients. These residual symptoms possess a high risk to relapse, chronic course, and even suicide [4]
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