Electrophysiology and Behavioral Assessment of the New Molecule SMe1EC2M3 as a Representative of the Future Class of Triple Reuptake Inhibitors

• Published in: Molecules (Basel, Switzerland) Switzerland), 2019-11, Vol.24 (23), p.4218
• Main Authors: Koprdova, Romana, Csatlosova, Kristina, Durisova, Barbora, Bogi, Eszter, Majekova, Magdalena, Dremencov, Eliyahu, Mach, Mojmir
• Format: Article
• Language: English
• Subjects: Animals; Antagonists; Antidepressants; Antidepressive Agents - chemistry; Antidepressive Agents - pharmacokinetics; Antidepressive Agents - pharmacology; behavior; Climbing; Dopamine; Dopamine D2 receptors; Dorsal raphe nucleus; Drug dosages; Electrophysiological Phenomena - drug effects; Electrophysiology; Haloperidol; In vivo methods and tests; Inhibitors; Intestinal absorption; Locus coeruleus; LSD; Lysergic acid diethylamide; Male; Mental depression; Neurons; Neurons - metabolism; Neurotransmitter Uptake Inhibitors - chemistry; Neurotransmitter Uptake Inhibitors - pharmacokinetics; Neurotransmitter Uptake Inhibitors - pharmacology; Norepinephrine; Permeability; Pharmacodynamics; Pharmacokinetics; Pharmacology; Psychotropic drugs; pyridoindole derivatives; Raphe nuclei; rat; Rats; Rats, Wistar; Serotonin; Serotonin S1 receptors; Swimming; Synaptic Transmission - drug effects; triple reuptake inhibitor; Ventral tegmentum; Yohimbine
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24234218

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-HT ; WAY100135), α-2 adrenergic (α , yohimbine), and dopamine-2 receptors (D , 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.