Recent advances in liquid chromatographic methods for the determination of selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors.

Depression is now the second largest public health burden throughout the world. Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) have replaced older antidepressants to become first-line medications to treat this disease with increased remission rates and markedly decreased incidence of severe adverse events. Traditional and modern bioanalytical strategies for SSRI and SNRI determination are being continuously improved. There has also been a recent increase in the use of unconventional sample preparation methods. This review critically evaluates the development of SSRI and SNRI liquid chromatographic analytical methods published between 2014 and mid-2019, with special attention to novel sample preparation methods.

Design, synthesis, and systematic evaluation of 4-arylpiperazine- and 4-benzylpiperidine napthyl ethers as inhibitors of monoamine neurotransmitters reuptake.

Two series of 4-arylpiperazine- and 4-benzylpiperidine naphthyl ethers were designed based on structure-activity relationship (SAR) and docking model of reported monoamine neurotransmitters reuptake inhibitors. The compounds were synthesized in 3-simple steps and their biological activities were evaluated. Several compounds were proven to be potent inhibitors of serotonin and norepinephrine reuptake. Computer docking was performed to study the interaction of the most potent compound 35 with human serotonin transporter. The results of the analyses suggest that 4-arylpiperazine- and 4-benzylpiperidine naphthyl ethers might be promising antidepressants worthy of further studies.

Duloxetine loaded-microemulsion system to improve behavioral activities by upregulating serotonin and norepinephrine in brain for the treatment of depression.

Duloxetine is a well-known antidepressant molecule which is used in the treatment of depression but due to poor solubility it suffers with the drawback of low oral bioavailability. The objective of present work was to formulate and characterize duloxetine loaded microemulsion to enhance the oral bioavailability. Prepared microemulsion was studied for droplet size, zeta potential, refractive index, polydispersity index (PDI), percentage transmittance, viscosity and in vitro release study. Optimized microemulsion (D1) showed spherical droplets with mean diameter of 35.40 ±â€¯3.11 nm, PDI of 0.170 and zeta potential values of -25.8 mV. Formulation showed good transmittance (greater than 99%), viscosity (0.205 Pa s) and refractive index (1.43 ±â€¯0.01). Increased duloxetine release was obtained with microemulsion in comparison to drug suspension. Behavioral tests like mobility test, tail suspension test and forced swimming test performed in depressed and treated rats with duloxetine microemulsion significantly improved the behavioral activities in comparison to duloxetine suspension. Pharmacokinetic studies showed that microemulsion exhibited 1.8 times increment in bioavailability in comparison to duloxetine suspension.

Efficacy of levomilnacipran extended release in treating major depressive disorder.

INTRODUCTION: Major depressive disorder (MDD) is the leading cause of disability worldwide with a heterogeneous symptom profile. Levomilnacipran extended release (ER) (Fetzima), a SNRI, has been approved by the Food and Drug Administration for treatment of MDD. While categorized as a SNRI, in contradistinction to other approved SNRIs, levomilnacipran exhibits differential affinity for the norepinephrine reuptake transporter when compared to the serotonin reuptake transporter. Areas covered: Completed clinical trials which focused on levomilnacipran ER administered in those with MDD were included in this drug evaluation. Expert opinion: Levomilnacipran ER, like all other first-line antidepressants exhibits significant efficacy in reducing total symptom severity. Levomilnacipran ER is particularly effective at improving measures of motivation, energy, and interest. Head to head comparative trials are not available with other antidepressants, and consequently, there are no claims of superior efficacy when compared to alternative antidepressants. Notwithstanding, it would be a viable and testable hypothesis that differential efficacy in favor of levomilnacipran may be obtained across select dimensions of depressive symptoms (e.g., fatigue and lack of motivation). Unfortunately, rigorous studies evaluating levomilnacipran for cognitive function in MDD have not been conducted. Levomilnacipran ER is generally well tolerated with minimal propensity for metabolic and weight disturbance.

Differentiating physicochemical properties between NDRIs and sNRIs clinically important for the treatment of ADHD.

BACKGROUND: Drugs available for treating attention-deficit hyperactivity disorder (ADHD) are mainly selective norepinephrine (sNRIs) and dual norepinephrine-dopamine (NDRIs) reuptake inhibitors. The major problem of sNRIs lines in their delayed onset of action and partial- or non-responses, which makes NDRIs distinguished in drug efficacy. Understanding of the differential binding modes of these 2 types of drugs to their corresponding targets can give great insights into the discovery of privileged drug-like scaffolds with improved efficacy. So far, no such study has been carried out. METHODS: A combinatorial computational strategy, integrating homology modeling, molecular docking, molecular dynamics (MD) and binding free energy calculation, was employed to analyze the binding modes of 8 clinically important ADHD drugs in their targets. RESULTS: Binding modes of 2 types of ADHD drugs (sNRIs and NDRIs) in their targets was identified for the first time by MD simulation, and 15 hot spot residues were discovered as crucial for NDRIs' binding in hNET and hDAT. Comparing to sNRIs, a clear reduction in the hydrophobic property of NDRIs' one functional group was observed, and the depth of drugs' aromatic ring stretched into the pocket of both targets was further identified as key contributors to drugs' selectivity. CONCLUSIONS: The hydrophobic property of NDRI ADHD drugs' one functional group contributes to their selectivity when bind hNET and hDAT. GENERAL SIGNIFICANCE: These results provide insights into NDRI ADHD drugs' binding mechanisms, which could be utilized as structural blueprints for assessing and discovering more efficacious drugs for ADHD therapy.

Antidepressant-like Effects of ZBH2012001, a Novel Potent Serotonin and Norepinephrine Reuptake Inhibitor.

AIMS: The present study was conducted to evaluate the antidepressant-like effects of ZBH2012001, a novel potential serotonin and norepinephrine reuptake inhibitor (SNRI). METHODS: Competitive binding assays, calcium flow, and cAMP detection methods were used to determine the affinity of ZBH2012001 for serotonin transporters (SERTs) and norepinephrine transporters (NETs), as well as its selectivity over dopamine transporters (DATs) and 16 other G-protein-coupled receptors (GPCRs) or iron channels. The antidepressant-like effects of ZBH2012001 were determined using the tail suspension test, forced swim test, and learned helplessness paradigm. The pharmacokinetics and acute toxicity of ZBH2012001 were also assessed. RESULTS: ZBH2012001 exhibited a moderate affinity to SERTs and NETs (Ki values were 35.3 ± 2.86 and 225 ± 26.0 nM, respectively); it had no effects on the DATs or the 16 other GPCRs or iron channels. Data from behavioral tests indicated that ZBH2012001 exhibited superior antidepressant-like effects compared with duloxetine (one of the most used SNRIs) in the three depression models. The pharmacokinetic evaluation of ZBH2012001 indicated that the absolute bioavailability value was 60.5%, and the acute toxicity test indicated that LD50 of ZBH2012001 was 346 mg/kg. CONCLUSION: These findings suggest that ZBH2012001 is a novel SNRI with superior antidepressant-like effects, lower acute toxicity and a better pharmacokinetic profile compared with duloxetine. Thus, ZBH2012001 may have potential therapeutic effects in depression disorders.

LEVOMILNACIPRAN--A SUCCESSOR OF MILNACIPRAN WITH A HIGHER NORADRENERGIC SELECTIVITY.

A new antidepressant, levomilnacipran, is the levorotatory enantiomer of milnacipran. The drug belongs to selective serotonin-norepinephrine reuptake inhibitors (SNRI) and has the highest noradrenergic selectivity of all members of this group of antidepressants. Clinical trials have confirmed the effectiveness of levomilnacipran in the treatment of depression. The drug was placed on the US market in the form of prolonged-release capsules, which greatly simplifies the treatment of psychiatric patients. The safety of the drug is also higher than the safety of a racemate, resulting in a beneficial impact on the therapeutic effect. In this paper we present current information on the pharmacological and clinical properties of the newest antidepressant--levomilnacipran.

Serotonin 6 receptor controls Alzheimer's disease and depression.

Alzheimer's disease (AD) and depression in late life are one of the most severe health problems in the world disorders. Serotonin 6 receptor (5-HT6R) has caused much interest for potential roles in AD and depression. However, a causative role of perturbed 5-HT6R function between two diseases was poorly defined. In the present study, we found that a 5-HT6R antagonist, SB271036 rescued memory impairment by attenuating the generation of Aß via the inhibition of γ-secretase activity and the inactivation of astrocytes and microglia in the AD mouse model. It was found that the reduction of serotonin level was significantly recovered by SB271036, which was mediated by an indirect regulation of serotonergic neurons via GABA. Selective serotonin reuptake inhibitor (SSRI), fluoxetine significantly improved cognitive impairment and behavioral changes. In human brain of depression patients, we then identified the potential genes, amyloid beta (A4) precursor protein-binding, family A, member 2 (APBA2), well known AD modulators by integrating datasets from neuropathology, microarray, and RNA seq. studies with correlation analysis tools. And also, it was demonstrated in mouse models and patients of AD. These data indicate functional network of 5-HT6R between AD and depression.

Design and synthesis of 4-benzylpiperidine carboxamides as dual serotonin and norepinephrine reuptake inhibitors.

A series of 4-benzylpiperidine carboxamides were designed and synthesized, and tested for their dual (serotonin and norepinephrine) reuptake inhibition. The synthesis of 4-benzylpiperidine carboxamides involved two main steps: amidation and substitution. Derivatives with 3 carbon linker displayed better activity than with 2 carbon linker. 4-Biphenyl- and 2-naphthyl-substituted derivatives 7e and 7j showed greater dual reuptake inhibition than standard drug venlafaxine HCl.

Design, synthesis and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitor.

Centrally acting noradrenaline reuptake inhibitor (NRI) is reportedly effective for patients with stress urinary incontinence (SUI) by increasing urethral closure in the clinical Phase IIa study with esreboxetine. Noradrenaline transporters are expressed in both central and peripheral nervous systems and the contribution of each site to efficacy has not been clarified. This report describes the development of a series of peripheral-selective 7-phenyl-1,4-oxazepane NRIs to investigate the contribution of the peripheral site to increasing urethral resistance in rats. (6S,7R)-1,4-Oxazepane derivative 7 exhibited noradrenaline transporter inhibition with high selectivity against inhibitions of serotonin and dopamine transporters. A replacement of hydroxyl with acetamide group contributed to enhancement of peripheral selectivity by increasing molecular polarity. Compound 12, N-{[(6S,7R)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methyl}acetamide 0.5 fumarate, which showed effectively no brain penetration in rats, increased urethral resistance in a dose-dependent manner and exhibited a maximal effect on par with esreboxetine. These results demonstrate that the urethral resistance-increasing effects of NRI in rats are mainly caused by the inhibition of noradrenaline transporters in the peripheral sites.