Design, Synthesis and Biological Evaluation of Novel Ketamine Derivatives as NMDAR Antagonists.

Depression is a chronic, severe, and often life-threatening neurological disorder. It not only causes depression in patients and affects daily life but, in severe cases, may lead to suicidal behavior and have adverse effects on families and society. In recent years, it has been found that sub-anesthetic doses of ketamine have a rapid antidepressant effect on patients with treatment-resistant depression and can significantly reduce the suicidal tendencies of patients with major depressive disorder. Current studies suggest that ketamine may exert antidepressant effects by blocking NMDAR ion channels, but its anesthetic and psychotomimetic side effects limit its application. Here, we report efforts to design and synthesize a novel series of ketamine derivatives of NMDAR antagonists, among which compounds 23 and 24 have improved activity compared with ketamine, introducing a new direction for the development of rapid-acting antidepressant drugs.

RE104: Synthesis and Activity of a Novel Serotonergic Psychedelic Prodrug of 4-Hydroxy-N,N-diisopropyltryptamine.

Results from randomized clinical trials of psilocybin in depressive disorders highlight the therapeutic potential of serotonergic psychedelic compounds in mental health disorders. The synthetic 5-hydroxytryptamine 2A receptor agonist 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT) is structurally similar to psilocin but is reported to have a shorter duration (2-3 h) of psychedelic effects, suggesting the potential for psilocybin-like therapeutic activity with reduced clinical resource burden. Here, we describe the preclinical and translational characterization of RE104, a 4-OH-DiPT prodrug comprising a glutarate moiety designed to cleave rapidly in situ and thus provide reasonable bioavailability of the active drug. Plasma concentration of 4-HO-DiPT over time in PK experiments in rats was correlated with head-twitch intensity. The half-life of 4-OH-DiPT was 40 min after subcutaneous administration of RE104 in rats. In a forced swim test, a single dose of RE104 (1 mg/kg) significantly reduced mean immobility time at 1 week compared with vehicle (P < 0.001), confirming translational antidepressant potential. Taken together, these data with RE104 show that the glutarate ester can act as an efficient prodrug strategy for 4-HO-DiPT, a unique short-duration psychedelic with potential in depressive disorders.

Pyrazoline Derivatives as Promising MAO-A Targeting Antidepressants: An Update.

Depression is one of the key conditions addressed by the Mental Health Gap Action Programme (mhGAP) of WHO that can lead to self-harm and suicide. Depression is associated with low levels of neurotransmitters, which eventually play a key role in the progression and development of mental illness. The nitrogen-containing heterocyclic compounds exhibit the most prominent pharmacological profile as antidepressants. Pyrazoline, a dihydro derivative of pyrazole, is a well-known five-membered heterocyclic moiety that exhibits a broad spectrum of biological activities. Many researchers have reported pyrazoline scaffold-containing molecules as potential antidepressant agents with selectivity for monoamine oxidase enzyme (MAO) isoforms. Several studies indicated a better affinity of pyrazoline-based moiety as (monoamine oxidase inhibitors) MAOIs. In this review, we have focused on the recent advancements (2019-2023) in the development of pyrazoline-containing derivatives exhibiting promising inhibition of MAO-A enzyme to treat depression. This review provides structural insights on pyrazoline-based molecules along with their SAR analysis, in silico exploration of binding interactions between pyrazoline derivatives and MAO-A enzyme, and clinical trial status of various drug molecules against depression. The in-silico exploration of potent pyrazoline derivatives at the active site of the MAOA enzyme will provide further insights into the development of new potential MAO-A inhibitors for the treatment of depression.

Synthesis and multifaceted pharmacological activity of novel quinazoline NHE-1 inhibitors.

The Na+/H+ exchanger isoform 1 (NHE-1) attracts ongoing attention as a validated drug target for the management of cardiovascular and ocular diseases owing to cytoprotective, anti-ischemic and anti-inflammatory properties of NHE-1 inhibitors. Herein we report novel NHE-1 inhibitors realized via functionalization of N1-alkyl quinazoline-2,4(1H,3H)-dione and quinazoline-4(3H)-one with N-acylguanidine or 3-acyl(5-amino-1,2,4-triazole) side chain. Lead compounds show activity in a nanomolar range. Their pharmacophoric features were elucidated with neural network modeling. Several compounds combine NHE-1 inhibition with antiplatelet activity. Compound 6b reduces intraocular pressure in rats and effectively inhibits the formation of glycated proteins. Compounds 3e and 3i inhibit pro-inflammatory activation of murine macrophages, LPS-induced interleukin-6 secretion and also exhibit antidepressant activity similar to amiloride. Hence, novel compounds represent an interesting starting point for the development of agents against cardiovascular diseases, thrombotic events, excessive inflammation, long-term diabetic complications and glaucoma.

A new class of 5-HT1A receptor antagonists with procognitive and antidepressant properties.

Aims: 5-HT1A receptor antagonists constitute a potential group of drugs in the treatment of CNS diseases. The aim of this study was to search for new procognitive and antidepressant drugs among amide derivatives of aminoalkanoic acids with 5-HT1A receptor antagonistic properties. Materials & methods: Thirty-three amides were designed and evaluated in silico for their drug-likeness. The synthesized compounds were tested in vitro for their 5-HT1A receptor affinity and functional profile. Moreover, their selectivity over 5-HT7, 5-HT2A and D2 receptors and ability to inhibit phosphodiesterases were evaluated. Results: A selected 5-HT1A receptor antagonist 20 (Ki = 35 nM, Kb = 4.9 nM) showed procognitive and antidepressant activity in vivo. Conclusion: Novel 5-HT1A receptor antagonists were discovered and shown as potential psychotropic drugs.

Development of tricyclic N-benzyl-4-hydroxybutanamide derivatives as inhibitors of GABA transporters mGAT1-4 with anticonvulsant, antinociceptive, and antidepressant activity.

γ-Aminobutyric acid (GABA) neurotransmission has a significant impact on the proper functioning of the central nervous system. Numerous studies have indicated that inhibitors of the GABA transporters mGAT1-4 offer a promising strategy for the treatment of several neurological disorders, including epilepsy, neuropathic pain, and depression. Following our previous results, herein, we report the synthesis, biological evaluation, and structure-activity relationship studies supported by molecular docking and molecular dynamics of a new series of N-benzyl-4-hydroxybutanamide derivatives regarding their inhibitory potency toward mGAT1-4. This study allowed us to identify compound 23a (N-benzyl-4-hydroxybutanamide bearing a dibenzocycloheptatriene moiety), a nonselective GAT inhibitor with a slight preference toward mGAT4 (pIC50 = 5.02 ± 0.11), and compound 24e (4-hydroxy-N-[(4-methylphenyl)-methyl]butanamide bearing a dibenzocycloheptadiene moiety) with relatively high inhibitory activity toward mGAT2 (pIC50 = 5.34 ± 0.09). In a set of in vivo experiments, compound 24e successively showed predominant anticonvulsant activity and antinociception in the formalin model of tonic pain. In contrast, compound 23a showed significant antidepressant-like properties in mice. These results were consistent with the available literature data, which indicates that, apart from seizure control, GABAergic neurotransmission is also involved in the pathophysiology of several psychiatric diseases, however alternative mechanisms underlying this action cannot be excluded. Finally, it is worth noting that the selected compounds showed unimpaired locomotor skills that have been indicated to give reliable results in behavioral assays.

Radioligand and computational insight in structure - Activity relationship of saccharin derivatives being ipsapirone and revospirone analogues.

Schizophrenia and depression are diseases that significantly impede human functioning in society. Current antidepressant drugs are not fully effective. According to literature data, the effect on D2R or 5-HT1AR can effectively reduce the symptoms of depression or schizophrenia. Recent research hypothetized that the synergism of both of these receptors can improve the effectiveness of therapy. Ipsapirone, a representative of long-chain arylpiperazines, is a known 5-HT1AR ligand that has antidepressant effect. This compound has no affinity for the D2R. Bearing in mind, we decided to design ligands with improved affinity to D2R and confirmed that in some cases elongation of the carbon linker or arylpiperazine exchange may have beneficial influence on the binding to D2R and 5-HT1AR. Four groups of ligands being ipsapirone analogues with butyl, pentyl, hexyl and stiffened xylene chains were designed. All compounds were obtained in solvent-free reactions supported by a microwave irradiation with an efficiency mainly above 60%. All ligands containing 1-(2-pyrimidinyl)piperazine exhibited high affinity to 5-HT1AR. In this case, chemical modifications within the chain did not affect the affinity to D2R. In the case of ligands containing 1-phenylpiperazine, 1-(3-trifluoromethylphenyl)piperazine, 1-(1-naphthyl)piperazine, and 1-(4-chlorophenyl)piperazine, elongation of carbon linker increases of affinity to D2R. For ligands containing 1- (2-pyridyl) piperazine, and 1-(2,3-dichlorophenyl)piperazine, we observed an opposite effect. For ligands containing 1-phenylpiperazine, 1-(2-methoxyphenyl)piperazine and 1-(2-pyridyl)piperazine, chain elongation had no effect on 5-HT1AR binding. In turn of ligands containing 1-(3-trifluoromethylphenyl)piperazine and 1- (2,3-dichlorophenyl)piperazine, we observed that elongation of carbon linker has a positive influence to 5-HT1AR. Molecular modelling was used to support the SAR study.

Piperazine, a Key Substructure for Antidepressants: Its Role in Developments and Structure-Activity Relationships.

Depression is the single largest contributor to global disability with a huge economic and social burden on the world. There are a number of antidepressant drugs on the market, but treatment-resistant depression and relapse of depression in a large number of patients have increased problems for clinicians. One peculiarity observed in most of the marketed antidepressants is the presence of a piperazine substructure. Although piperazine is also used in the optimization of other pharmacological agents, it is almost extensively used for the development of novel antidepressants. One common understanding is that this is due to its favorable CNS pharmacokinetic profile; however, in the case of antidepressants, piperazine plays a much bigger role and is involved in specific binding conformations of these agents. Therefore, in this review, a critical analysis of the significance of the piperazine moiety in the development of antidepressants has been performed. An overview of current developments in the designing and synthesis of piperazine-based antidepressants (2015 onwards) along with SAR studies is also provided. The various piperazine-based therapeutic agents in early- or late-phase human testing for depression are also discussed. The preclinical compounds discussed in this review will help researchers understand how piperazine actually influences the design and development of novel antidepressant compounds. The SAR studies discussed will provide crucial clues about the structural features and optimizations required to enhance the efficacy and potency of piperazine-based antidepressants.

New 2-Pyrazoline and Hydrazone Derivatives as Potent and Selective Monoamine Oxidase A Inhibitors.

Thirty compounds having 1-[2-(5-substituted-2-benzoxazolinone-3-yl) acetyl]-3,5-disubstitutedphenyl-2-pyrazoline structure and nine compounds having N'-(1,3-disubstitutedphenylallylidene)-2-(5-substituted-2-benzoxazolinone-3-yl)acetohydrazide skeleton were synthesized and evaluated as monoamine oxidase (MAO) inhibitors. All of the compounds exhibited selective MAO-A inhibitor activity in the nanomolar or low micromolar range. The results of the molecular docking for hydrazone derivatives supported the in vitro results. Five compounds, 6 (0.008 µM, Selectivity Index (SI): 9.70 × 10-4), 7 (0.009 µM, SI: 4.55 × 10-5), 14 (0.001 µM, SI: 8.00 × 10-4), 21 (0.009 µM, SI: 1.37 × 10-5), and 42 (0.010 µM, SI: 5.40 × 10-6), exhibiting the highest inhibition and selectivity toward hMAO-A and nontoxic to hepatocytes were assessed for antidepressant activity as acute and subchronic in mice. All of these five compounds showed significant antidepressant activity with subchronic administration consistent with the increase in the brain serotonin levels and the compounds crossed the blood-brain barrier according to parallel artificial membrane permeation assay. Compounds 14, 21, and 42 exhibited an ex vivo MAO-A profile, which is highly consistent with the in vitro data.

Molecular evolution of a cytochrome P450 for the synthesis of potential antidepressant (2R,6R)-hydroxynorketamine.

Saturation mutagenesis at seven first-sphere residues of the cytochrome P450 monooxygenase 154E1 (CYP154E1) from Thermobifida fusca YX was applied to construct a variant with only three substitutions that enabled the effective two-step synthesis of the potential antidepressant (2R,6R)-hydroxynorketamine. A recombinant E. coli whole-cell system was essential for GC/MS based medium-throughput screening and at the same time facilitated the oxidation of the substrate (R)-ketamine at a higher scale for product isolation and subsequent NMR analysis.

Nine prenylated acylphloroglucinols with potential anti-depressive and hepatoprotective activities from Hypericum scabrum.

In our screening program for new biologically active secondary metabolites, nine new polycyclic polyprenyled acylphloroglucinols, hyperscabins D-L, together with three known compounds, were obtained from the aerial parts of Hypericum scabrum. The chemical structures of 1-9 were characterized by extensive spectroscopic analyses, nuclear magnetic resonance calculation with DP4+ probability analysis, and the electronic circular dichroism spectra were calculated. Compound 1 was an unusual prenylated acylphloroglucinol decorated with a 5-oxaspiro [4,5] deca-1,9-dione skeleton. Compound 2 was a newly identified spirocyclic polyprenylated acylphloroglucinol possessing a rare 5,5-spiroketal segment. Compounds 3, 8, and 10 (10 µM) exhibited pronounced hepatoprotective activity against d-galactosamine-induced WB-F344 cell damage in vitro assays. All test compounds (1, 3, and 7-12) demonstrated potential inhibitory effects at 10 µM against noradrenalinet ([3H]-NE) reuptake in rat brain synaptosome.

Synthesis of ring-opened derivatives of triazole-containing quinolinones and their antidepressant and anticonvulsant activities.

Based on the potent antidepressant and anticonvulsant activities of the triazole-containing quinolinones reported in our previous work, a series of ring-opened derivatives of them were designed, synthesized in this work. Their antidepressant and anticonvulsant activities were screened using the forced swimming test (FST) and the maximal electroshock seizure test (MES), respectively. The results showed that compounds 4a, 5a, 6c-6e, 6g-6i, and 7 led to significant reductions in the accumulated immobility time in the FST at a dose of 50 mg/kg. Especially compound 7 exhibited higher levels of efficacy than the reference standard fluoxetine in the FST and the tail suspension test. The results of an open field test excluded the possibility of central nervous stimulation of 7, which further confirmed its antidepressant effect. Meanwhile, compounds 6a-6i and 7 showed different degrees of anticonvulsant activity in mice at the doses range from 300 to 30 mg/kg in the MES. Among them, compounds 6e and 7 displayed the ED50 of 38.5 and 32.7 mg/kg in the MES, and TD50 of 254.6 and 245.5 mg/kg, respectively. No one showed neurotoxicity at the dose of 100 mg/kg. The preliminary investigation forward to their mechanism indicated that regulation of GABAergic system might contribute to their anticonvulsive and anti-depressive action.

Di-aryl guanidinium derivatives: Towards improved α2-Adrenergic affinity and antagonist activity.

Compounds with excellent receptor engagement displaying α2-AR antagonist activity are useful not only for therapeutic purposes (e.g. antidepressants), but also to help in the crystallization of this particular GPCR. Therefore, based on our broad experience in the topic, we have prepared eighteen di-aryl (phenyl and/or pyridin-2-yl) mono- or di-substituted guanidines and 2-aminoimidazolines. The in vitro α2-AR binding affinity experiments in human brain tissue showed the advantage of a 2-aminoimidazolinium cation, a di-arylmethylene core, a conformationally locked pyridin-2-yl-guanidine and a di-substituted guanidinium to achieve good α2-AR engagement. After different in vitro [35S]GTPγS binding experiments in human prefrontal cortex tissue, it was possible to identify that compounds 7a, 7b and 7c were α2-AR partial agonist, whereas 8h was a potent α2-AR antagonist. Docking and MD studies with a model of α2A-AR and two crystal structures suggest that antagonism is achieved by compounds carrying a di-substituted guanidine which substituent occupy a pocket adjacent to TM5 without engaging S2005.42 or S2045.46, and a mono-substituted cationic group, which favorably interacts with E942.65.

Novel piperazine-2,5-dione analogs bearing 1H-indole: Synthesis and biological effects.

In this work, a series of novel piperazine-2,5-dione derivatives bearing indole analogs (2a-2q) was designed and synthesized. The synthesized compounds were characterized by IR, 1H NMR, 13C NMR spectroscopy, and ESI-MS. They were then evaluated for their anti-depressant, anti-inflammatory, and analgesic activities in vivo. The experimental results revealed that all the compounds showed clear anti-depressant, anti-inflammatory, and analgesic effects at a dose of 10 mg/kg. Among them, compounds 2e and 2q exhibited the best anti-depressant effects (the percent decreases in the duration of immobility were 70.2% and 71.2%, respectively), which were similar to that of fluoxetine (67.9%) in the forced swim test. Additionally, compounds 2e and 2q also displayed good anti-inflammatory and analgesic activities. Literature reports have highlighted the anti-inflammatory and analgesic effects of anti-depressant drugs, suggesting that they may have a similar mechanism of action. Therefore, further studies to investigate the possible mechanisms of action of compounds 2e and 2q are warranted.

Synthesis, in vitro evaluation and molecular docking of a new class of indolylpropyl benzamidopiperazines as dual AChE and SERT ligands for Alzheimer's disease.

During the last decade, the one drug-one target strategy has resulted to be inefficient in facing diseases with complex ethiology like Alzheimer's disease and many others. In this context, the multitarget paradigm has emerged as a promising strategy. Based on this consideration, we aim to develop novel molecules as promiscuous ligands acting in two or more targets at the same time. For such purpose, a new series of indolylpropyl-piperazinyl oxoethyl-benzamido piperazines were synthesized and evaluated as multitarget-directed drugs for the serotonin transporter (SERT) and acetylcholinesterase (AChE). The ability to decrease ß-amyloid levels as well as cell toxicity of all compounds were also measured. In vitro results showed that at least four compounds displayed promising activity against SERT and AChE. Compounds 18 and 19 (IC50 = 3.4 and 3.6 µM respectively) exhibited AChE inhibition profile in the same order of magnitude as donepezil (DPZ, IC50 = 2.17 µM), also displaying nanomolar affinity in SERT. Moreover, compounds 17 and 24 displayed high SERT affinities (IC50 = 9.2 and 1.9 nM respectively) similar to the antidepressant citalopram, and significant micromolar AChE activity at the same time. All the bioactive compounds showed a low toxicity profile in the range of concentrations studied. Molecular docking allowed us to rationalize the binding mode of the synthesized compounds in both targets. In addition, we also show that compounds 11 and 25 exhibit significant ß-amyloid lowering activity in a cell-based assay, 11 (50% inhibition, 10 µM) and 25 (35% inhibition, 10 µM). These results suggest that indolylpropyl benzamidopiperazines based compounds constitute promising leads for a multitargeted approach for Alzheimer's disease.

Discovery of δ opioid receptor full agonists lacking a basic nitrogen atom and their antidepressant-like effects.

We have recently reported that the elaboration of the N-substituent in the δ opioid receptor (DOR) antagonist naltrindole (NTI) enabled the regulation of the DOR activities from full inverse agonists to weak partial agonists. The investigations of amide-type NTI derivatives revealed that N-phenylacetyl and N-dihydrocinnamoyl derivatives 3a and 3b were DOR full agonists. The same transformations were applied to a DOR agonist KNT-127 to provide the more potent DOR agonists 6a and 6b. Among the tested compounds, the most efficacious compound 6a showed dose-dependent antidepressant-like effects in the mouse forced swim test. The antidepressant-like effects by 6a seemed to be more potent than those of KNT-127, which is a more potent DOR agonist in in vitro assays. The amide-type compound like 6a may more fully penetrate into the central nervous system.

Stereoselective Activity of 1-Propargyl-4-styrylpiperidine-like Analogues That Can Discriminate between Monoamine Oxidase Isoforms A and B.

The resurgence of interest in monoamine oxidases (MAOs) has been fueled by recent correlations of this enzymatic activity with cardiovascular, neurological, and oncological disorders. This has promoted increased research into selective MAO-A and MAO-B inhibitors. Here, we shed light on how selective inhibition of MAO-A and MAO-B can be achieved by geometric isomers of cis- and trans-1-propargyl-4-styrylpiperidines. While the cis isomers are potent human MAO-A inhibitors, the trans analogues selectively target only the MAO-B isoform. The inhibition was studied by kinetic analysis, UV-vis spectrum measurements, and X-ray crystallography. The selective inhibition of the MAO-A and MAO-B isoforms was confirmed ex vivo in mouse brain homogenates, and additional in vivo studies in mice show the therapeutic potential of 1-propargyl-4-styrylpiperidines for central nervous system disorders. This study represents a unique case of stereoselective activity of cis/trans isomers that can discriminate between structurally related enzyme isoforms.

Discovery of Potent, Selective, and Direct Acid Sphingomyelinase Inhibitors with Antidepressant Activity.

Recent studies on sphingolipids suggest that acid sphingomyelinase (ASM), which plays a central role in the pathogenesis of major depression, is emerging to be a novel target for developing antidepressants. Herein we first described the design, synthesis, and biological evaluation of hydroxamic acid-based direct inhibitors of ASM with the effort of validating their antidepressant effects in vivo. As a result, a series of novel ASM inhibitors were developed using a structure-based approach. Our studies demonstrated that the administration of 21b improved depression-like behaviors of rats. Importantly, this positive result was relevant to the inhibition of ASM and the increasing neurogenesis in hippocampus. To the best of our knowledge, this is the first time that direct inhibitors of ASM were developed to support the possibility of ASM as a potential therapeutic target for depression.

Synthesis and Evaluation on Anticonvulsant and Antidepressant Activities of Naphthoquinone Derivatives Containing Pyrazole and Pyrimidine Fragments.

Novel heterocyclic dichloronaphthoquinone derivatives have been synthesized by chlorine atom substitution in 2,3-dichloro-1,4-naphthoquinone to pyrazole or pyrimidine fragments. The structures of these compounds have been confirmed by FT-IR, ESI-MS, 1H?NMR, 13C-NMR and elementary analysis. Synthesized compounds were evaluated for their anticonvulsant action in a pentylenetetrazole (PTZ)-convulsion model and antidepressant activity in the forced swimming test (FST). All naphthoquinone derivatives at a dose 100 mg/kg indicated anticonvulsant effect in PTZ-induced test at 3 h and 24 h after oral administration. In addition, these compounds possessed prolonged antidepressant properties significantly reducing the duration of immobility time when compared to the reference drug amitriptyline.

Carbamoylated erythropoietin produces antidepressant-like effects in male and female mice.

Major depressive disorder and related illnesses are globally prevalent, with a significant risk for suicidality if untreated. Antidepressant drugs that are currently prescribed do not benefit 30% of treated individuals. Furthermore, there is a delay of 3 or more weeks before a reduction in symptoms. Results from preclinical studies have indicated an important role for trophic factors in regulating behavior. Erythropoietin (Epo), which is widely prescribed for anemia, has been shown to produce robust neurotrophic actions in the CNS. Although Epo's antidepressant activity has been successfully demonstrated in multiple clinical trials, the inherent ability to elevate RBC counts and other hematological parameters preclude its development as a mainstream CNS drug. A chemically engineered derivative, carbamoylated Epo (Cepo) has no hematological activity, but retains the neurotrophic actions of Epo. Cepo is therefore an attractive candidate to be tested as an antidepressant. OBJECTIVE: To evaluate the antidepressant properties of Cepo in established antidepressant-responsive rodent behavioral assays. METHODS: Adult male and female BALB/c mice were used for this study. Cepo (30 µgrams/ kg BWT) or vehicle (PBS) was administered intraperitoneally for 4 days before the test of novelty induced hypophagia and subsequently at five hours before testing in forced swim test (FST), tail suspension test (TST) and open field test (OFT). To obtain mechanistic insight we examined the phosphorylation of the transcription factor cAMP response element binding protein (CREB). RESULTS: Administration of Cepo at 30 µgrams/ kg BWT, for 4 days produced significant reduction in latency to consume a palatable drink in a novel environment in male and female mice. Male BALB/c mice had a significant reduction in immobility in both tail suspension and forced swim tests, and female mice exhibited lower immobility in the forced swim test.