Recent advances in dopamine D2 receptor ligands in the treatment of neuropsychiatric disorders.

Dopamine is a biologically active amine synthesized in the central and peripheral nervous system. This biogenic monoamine acts by activating five types of dopamine receptors (D1-5 Rs), which belong to the G protein-coupled receptor family. Antagonists and partial agonists of D2 Rs are used to treat schizophrenia, Parkinson's disease, depression, and anxiety. The typical pharmacophore with high D2 R affinity comprises four main areas, namely aromatic moiety, cyclic amine, central linker and aromatic/heteroaromatic lipophilic fragment. From the literature reviewed herein, we can conclude that 4-(2,3-dichlorophenyl), 4-(2-methoxyphenyl)-, 4-(benzo[b]thiophen-4-yl)-1-substituted piperazine, and 4-(6-fluorobenzo[d]isoxazol-3-yl)piperidine moieties are critical for high D2 R affinity. Four to six atoms chains are optimal for D2 R affinity with 4-butoxyl as the most pronounced one. The bicyclic aromatic/heteroaromatic systems are most frequently occurring as lipophilic appendages to retain high D2 R affinity. In this review, we provide a thorough overview of the therapeutic potential of D2 R modulators in the treatment of the aforementioned disorders. In addition, this review summarizes current knowledge about these diseases, with a focus on the dopaminergic pathway underlying these pathologies. Major attention is paid to the structure, function, and pharmacology of novel D2 R ligands, which have been developed in the last decade (2010-2021), and belong to the 1,4-disubstituted aromatic cyclic amine group. Due to the abundance of data, allosteric D2 R ligands and D2 R modulators from patents are not discussed in this review.

Neurotoxicity evoked by organophosphates and available countermeasures.

Organophosphorus compounds (OP) are a constant problem, both in the military and in the civilian field, not only in the form of acute poisoning but also for their long-lasting consequences. No antidote has been found that satisfactorily protects against the toxic effects of organophosphates. Likewise, there is no universal cure to avert damage after poisoning. The key mechanism of organophosphate toxicity is the inhibition of acetylcholinesterase. The overstimulation of nicotinic or muscarinic receptors by accumulated acetylcholine on a synaptic cleft leads to activation of the glutamatergic system and the development of seizures. Further consequences include generation of reactive oxygen species (ROS), neuroinflammation, and the formation of various other neuropathologists. In this review, we present neuroprotection strategies which can slow down the secondary nerve cell damage and alleviate neurological and neuropsychiatric disturbance. In our opinion, there is no unequivocal approach to ensure neuroprotection, however, sooner the neurotoxicity pathway is targeted, the better the results which can be expected. It seems crucial to target the key propagation pathways, i.e., to block cholinergic and, foremostly, glutamatergic cascades. Currently, the privileged approach oriented to stimulating GABAAR by benzodiazepines is of limited efficacy, so that antagonizing the hyperactivity of the glutamatergic system could provide an even more efficacious approach for terminating OP-induced seizures and protecting the brain from permanent damage. Encouraging results have been reported for tezampanel, an antagonist of GluK1 kainate and AMPA receptors, especially in combination with caramiphen, an anticholinergic and anti-glutamatergic agent. On the other hand, targeting ROS by antioxidants cannot or already developed neuroinflammation does not seem to be very productive as other processes are also involved.

A-agents, misleadingly known as "Novichoks": a narrative review.

"Novichok" refers to a new group of nerve agents called the A-series agents. Their existence came to light in 2018 after incidents in the UK and again in 2020 in Russia. They are unique organophosphorus-based compounds developed during the Cold War in a program called Foliant in the USSR. This review is based on original chemical entities from Mirzayanov's memoirs published in 2008. Due to classified research, a considerable debate arose about their structures, and hence, various structural moieties were speculated. For this reason, the scientific literature is highly incomplete and, in some cases, contradictory. This review critically assesses the information published to date on this class of compounds. The scope of this work is to summarize all the available and relevant information, including the physicochemical properties, chemical synthesis, mechanism of action, toxicity, pharmacokinetics, and medical countermeasures used to date. The environmental stability of A-series agents, the lack of environmentally safe decontamination, their high toxicity, and the scarcity of information on post-contamination treatment pose a challenge for managing possible incidents.

Differentiated SH-SY5Y neuroblastoma cells as a model for evaluation of nerve agent-associated neurotoxicity.

Organophosphorus compounds (OPs) involving life-threatening nerve agents (NA) have been known for several decades. Despite a clear mechanism of their lethality caused by the irreversible inhibition of acetylcholinesterase (AChE) and manifested via overstimulation of peripheral nicotinic and muscarinic acetylcholine (ACh) receptors, the mechanism for central neurotoxicity responsible for acute or delayed symptoms of the poisoning has not been thoroughly uncovered. One of the reasons is the lack of a suitable model. In our study, we have chosen the SH-SY5Y model in both the differentiated and undifferentiated state to study the effects of NAs (GB, VX and A234). The activity of expressed AChE in cell lysate assessed by Ellman's method showed 7.3-times higher activity in differentiated SH-SY5Y cells in contrast to undifferentiated cells, and with no involvement of BuChE as proved by ethopropazine (20 µM). The activity of AChE was found to be, in comparison to untreated cells, 16-, 9.3-, and 1.9-times lower upon A234, VX, and GB (100 µM) administration respectively. The cytotoxic effect of given OPs expressed as the IC50 values for differentiated and undifferentiated SH-SY5Y, respectively, was found 12 mM and 5.7 mM (A234), 4.8 mM and 1.1 mM (VX) and 2.6 mM and 3.8 mM (GB). In summary, although our results confirm higher AChE expression in the differentiated SH-SY5Y cell model, the such higher expression does not lead to a more pronounced NA cytotoxic effect. On the contrary, higher expression of AChE may attenuate NA-induced cytotoxicity by scavenging the NA. Such finding highlights a protective role for cholinesterases by scavenging Novichoks (A-agents). Second, we confirmed the mechanism of cytotoxicity of NAs, including A-agents, can be ascribed rather to the non-specific effects of OPs than to AChE-mediated effects.

Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK).

Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are two structurally related families of kinases that play vital roles in cell growth and DNA damage repair. Dysfunction of PIKK members and aberrant stimulation of the PI3K/AKT/mTOR signalling pathway are linked to a plethora of diseases including cancer. In recent decades, numerous inhibitors related to the PI3K/AKT/mTOR signalling have made great strides in cancer treatment, like copanlisib and sirolimus. Notably, most of the PIKK inhibitors (such as VX-970 and M3814) related to DNA damage response have also shown good efficacy in clinical trials. However, these drugs still require a suitable combination therapy to overcome drug resistance or improve antitumor activity. Based on the aforementioned facts, we summarised the efficacy of PIKK, PI3K, and AKT inhibitors in the therapy of human malignancies and the resistance mechanisms of targeted therapy, in order to provide deeper insights into cancer treatment.

Structure-Guided Design of N-Methylpropargylamino-Quinazoline Derivatives as Multipotent Agents for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex disease with an unknown etiology. Available treatments, limited to cholinesterase inhibitors and N-methyl-d-aspartate receptor (NMDAR) antagonists, provide symptomatic relief only. As single-target therapies have not proven effective, rational specific-targeted combination into a single molecule represents a more promising approach for treating AD, and is expected to yield greater benefits in alleviating symptoms and slowing disease progression. In the present study, we designed, synthesized, and biologically evaluated 24 novel N-methylpropargylamino-quinazoline derivatives. Initially, compounds were thoroughly inspected by in silico techniques determining their oral and CNS availabilities. We tested, in vitro, the compounds' effects on cholinesterases and monoamine oxidase A/B (MAO-A/B), as well as their impacts on NMDAR antagonism, dehydrogenase activity, and glutathione levels. In addition, we inspected selected compounds for their cytotoxicity on undifferentiated and differentiated neuroblastoma SH-SY5Y cells. We collectively highlighted II-6h as the best candidate endowed with a selective MAO-B inhibition profile, NMDAR antagonism, an acceptable cytotoxicity profile, and the potential to permeate through BBB. The structure-guided drug design strategy applied in this study imposed a novel concept for rational drug discovery and enhances our understanding on the development of novel therapeutic agents for treating AD.

Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities.

Twenty-four novel compounds bearing tetrahydroacridine and N-propargyl moieties have been designed, synthesised, and evaluated in vitro for their anti-cholinesterase and anti-monoamine oxidase activities. Propargyltacrine 23 (IC50 = 21 nM) was the most potent acetylcholinesterase (AChE) inhibitor, compound 20 (IC50 = 78 nM) showed the best inhibitory human butyrylcholinesterase (hBChE) profile, and ligand 21 afforded equipotent and significant values on both ChEs (human AChE [hAChE]: IC50 = 0.095 ± 0.001 µM; hBChE: IC50 = 0.093 ± 0.003 µM). Regarding MAO inhibition, compounds 7, 15, and 25 demonstrated the highest inhibitory potential towards hMAO-B (IC50 = 163, 40, and 170 nM, respectively). In all, compounds 7, 15, 20, 21, 23, and 25 exhibiting the most balanced pharmacological profile, were submitted to permeability and cell viability tests. As a result, 7-phenoxy-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroacridin-9-amine hydrochloride (15) has been identified as a permeable agent that shows a balanced pharmacological profile [IC50 (hAChE) = 1.472 ± 0.024 µM; IC50 (hBChE) = 0.659 ± 0.077 µM; IC50 (hMAO-B) = 40.39 ± 5.98 nM], and consequently, as a new hit-ligand that deserves further investigation, in particular in vivo analyses, as the preliminary cell viability test results reported here suggest that this is a relatively safe therapeutic agent.

Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: N-Functionalization Determines the Multitarget Anti-Alzheimer's Activity Profile.

Using two ways of functionalizing amiridine-acylation with chloroacetic acid chloride and reaction with thiophosgene-we have synthesized new homobivalent bis-amiridines joined by two different spacers-bis-N-acyl-alkylene (3) and bis-N-thiourea-alkylene (5) -as potential multifunctional agents for the treatment of Alzheimer's disease (AD). All compounds exhibited high inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity for BChE. These new agents displayed negligible carboxylesterase inhibition, suggesting a probable lack of untoward drug-drug interactions arising from hydrolytic biotransformation. Compounds 3 with bis-N-acyl-alkylene spacers were more potent inhibitors of both cholinesterases compared to compounds 5 and the parent amiridine. The lead compounds 3a-c exhibited an IC50(AChE) = 2.9-1.4 µM, IC50(BChE) = 0.13-0.067 µM, and 14-18% propidium displacement at 20 µM. Kinetic studies of compounds 3a and 5d indicated mixed-type reversible inhibition. Molecular docking revealed favorable poses in both catalytic and peripheral AChE sites. Propidium displacement from the peripheral site by the hybrids suggests their potential to hinder AChE-assisted Aß42 aggregation. Conjugates 3 had no effect on Aß42 self-aggregation, whereas compounds 5c-e (m = 4, 5, 6) showed mild (13-17%) inhibition. The greatest difference between conjugates 3 and 5 was their antioxidant activity. Bis-amiridines 3 with N-acylalkylene spacers were nearly inactive in ABTS and FRAP tests, whereas compounds 5 with thiourea in the spacers demonstrated high antioxidant activity, especially in the ABTS test (TEAC = 1.2-2.1), in agreement with their significantly lower HOMO-LUMO gap values. Calculated ADMET parameters for all conjugates predicted favorable blood-brain barrier permeability and intestinal absorption, as well as a low propensity for cardiac toxicity. Thus, it was possible to obtain amiridine derivatives whose potencies against AChE and BChE equaled (5) or exceeded (3) that of the parent compound, amiridine. Overall, based on their expanded and balanced pharmacological profiles, conjugates 5c-e appear promising for future optimization and development as multitarget anti-AD agents.

Huprine Y - Tryptophan heterodimers with potential implication to Alzheimer's disease treatment.

The search for novel and effective therapeutics for Alzheimer's disease (AD) is the main quest that remains to be resolved. The goal is to find a disease-modifying agent able to confront the multifactorial nature of the disease positively. Herewith, a family of huprineY-tryptophan heterodimers was prepared, resulting in inhibition of cholinesterase and neuronal nitric oxide synthase enzymes, with effect against amyloid-beta (Aß) and potential ability to cross the blood-brain barrier. Their cholinesterase pattern of behavior was inspected using kinetic analysis in tandem with docking studies. These heterodimers exhibited a promising pharmacological profile with strong implication in AD.

Derivatives of montanine-type alkaloids and their implication for the treatment of Alzheimer's disease: Synthesis, biological activity and in silico study.

Alzheimers disease (AD) is the most common neurodegenerative disorder, characterized by neuronal loss and cognitive impairment. Currently, very few drugs are available for AD treatment, and a search for new therapeutics is urgently needed. Thus, in the current study, twenty-eight new derivatives of montanine-type Amaryllidaceae alkaloids were synthesized and evaluated for their ability to inhibit human recombinant acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE). Three derivatives (1n, 1o, and 1p) with different substitution patterns demonstrated significant selective inhibitory potency for hAChE (IC50 < 5 µM), and one analog, 1v, showed selective hBuChE inhibition activity (IC50 = 1.73 ± 0.05 µM). The prediction of CNS availability, as disclosed by the BBB score, suggests that the active compounds in this survey should be able pass through the blood-brain barrier (BBB). Cytotoxicity screening and docking studies were carried out for the two most pronounced cholinesterase inhibitors, 1n and 1v.

Alkaloids of Zephyranthes citrina (Amaryllidaceae) and their implication to Alzheimer's disease: Isolation, structural elucidation and biological activity.

Twenty known Amaryllidaceae alkaloids of various structural types, and one undescribed alkaloid of narcikachnine-type, named narcieliine (3), have been isolated from fresh bulbs of Zephyranthes citrina. The chemical structures of the isolated alkaloids were elucidated by a combination of MS, HRMS, 1D and 2D NMR, and CD spectroscopic techniques, and by comparison with literature data. The absolute configuration of narcieliine (3) has also been determined. Compounds isolated in a sufficient quantity were evaluated for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7), butyrylcholinesterase (BuChE; E.C. 3.1.1.8), and prolyl oligopeptidase (POP; E.C. 3.4.21.26) inhibition activities. Significant human AChE/BuChE (hAChE/hBuChE) inhibitory activity was demonstrated by the newly described alkaloid narcieliine (3), with IC50 values of 18.7 ± 2.3 µM and 1.34 ± 0.31 µM, respectively. This compound is also predicted to cross the blood-brain barrier (BBB) through passive diffusion. The in vitro data were further supported by in silico studies of 3 in the active site of hAChE/hBuChE.

Amiridine-piperazine hybrids as cholinesterase inhibitors and potential multitarget agents for Alzheimer's disease treatment.

We synthesized eleven new amiridine-piperazine hybrids 5a-j and 7 as potential multifunctional agents for Alzheimer's disease (AD) treatment by reacting N-chloroacetylamiridine with piperazines. The compounds displayed mixed-type reversible inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Conjugates were moderate inhibitors of equine and human BChE with negligible fluctuation in anti-BChE activity, whereas anti-AChE activity was substantially dependent on N4-substitution of the piperazine ring. Compounds with para-substituted aromatic moieties (5g, 5h, and bis-amiridine 7) had the highest anti-AChE activity in the low micromolar range. Top-ranked compound 5h, N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-9-yl)-2-[4-(4-nitro-phenyl)-piperazin-1-yl]-acetamide, had an IC50 for AChE = 1.83 ± 0.03 µM (Ki = 1.50 ± 0.12 and αKi = 2.58 ± 0.23 µM). The conjugates possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. In agreement with analysis of inhibition kinetics and molecular modeling studies, the lead compounds were found to bind effectively to the peripheral anionic site of AChE and displace propidium, indicating their potential to block AChE-induced ß-amyloid aggregation. Similar propidium displacement activity was first shown for amiridine. Two compounds, 5c (R = cyclohexyl) and 5e (R = 2-MeO-Ph), exhibited appreciable antioxidant capability with Trolox equivalent antioxidant capacity values of 0.47 ± 0.03 and 0.39 ± 0.02, respectively. Molecular docking and molecular dynamics simulations provided insights into the structure-activity relationships for AChE and BChE inhibition, including the observation that inhibitory potencies and computed pKa values of hybrids were generally lower than those of the parent molecules. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters comparable to those of amiridine and therefore acceptable for potential lead compounds at the early stages of anti-AD drug development.

Tacrine - Benzothiazoles: Novel class of potential multitarget anti-Alzheimers drugs dealing with cholinergic, amyloid and mitochondrial systems.

A series of tacrine - benzothiazole hybrids incorporate inhibitors of acetylcholinesterase (AChE), amyloid ß (Aß) aggregation and mitochondrial enzyme ABAD, whose interaction with Aß leads to mitochondrial dysfunction, into a single molecule. In vitro, several of 25 final compounds exerted excellent anti-AChE properties and interesting capabilities to block Aß aggregation. The best derivative of the series could be considered 10w that was found to be highly potent and selective towards AChE with the IC50 value in nanomolar range. Moreover, the same drug candidate exerted absolutely the best results of the series against ABAD, decreasing its activity by 23% at 100 µM concentration. Regarding the cytotoxicity profile of highlighted compound, it roughly matched that of its parent compound - 6-chlorotacrine. Finally, 10w was forwarded for in vivo scopolamine-induced amnesia experiment consisting of Morris Water Maze test, where it demonstrated mild procognitive effect. Taking into account all in vitro and in vivo data, highlighted derivative 10w could be considered as the lead structure worthy of further investigation.

Development of versatile and potent monoquaternary reactivators of acetylcholinesterase.

To date, the only treatments developed for poisoning by organophosphorus compounds, the most toxic chemical weapons of mass destruction, have exhibited limited efficacy and versatility. The available causal antidotes are based on reactivation of the enzyme acetylcholinesterase (AChE), which is rapidly and pseudo-irreversibly inhibited by these agents. In this study, we developed a novel series of monoquaternary reactivators combining permanently charged moieties tethered to position 6- of 3-hydroxypyridine-2-aldoxime reactivating subunit. Highlighted representatives (21, 24, and 27; also coded as K1371, K1374, and K1375, respectively) that contained 1-phenylisoquinolinium, 7-amino-1-phenylisoquinolinium and 4-carbamoylpyridinium moieties as peripheral anionic site ligands, respectively, showed efficacy superior or comparable to that of the clinically used standards. More importantly, these reactivators exhibited wide-spectrum efficacy and were minutely investigated via determination of their reactivation kinetics in parallel with molecular dynamics simulations to study their mechanisms of reactivation of the tabun-inhibited AChE conjugate. To further confirm the potential applicability of these candidates, a mouse in vivo assay was conducted. While K1375 had the lowest acute toxicity and the most suitable pharmacokinetic profile, the oxime K1374 with delayed elimination half-life was the most effective in ameliorating the signs of tabun toxicity. Moreover, both in vitro and in vivo, the versatility of the agents was substantially superior to that of clinically used standards. Their high efficacy and broad-spectrum capability make K1374 and K1375 promising candidates that should be further investigated for their potential as nerve agents and insecticide antidotes.

Tacrine and its 7-methoxy derivate; time-change concentration in plasma and brain tissue and basic toxicological profile in rats.

The search for tacrine derivatives, as potential Alzheimer´s disease treatment, is still being at the forefront of scientific efforts. 7-MEOTA was found to be a potent, centrally active acetylcholinesterase inhibitor free of the serious side effects observed for tacrine. Unfortunately, a relevant argumentation about pharmacokinetics and potential toxicity is incomplete; information about tacrine derivatives absorption and especially CNS penetration are still rare as well as detailed toxicological profile in vivo. Although the structural changes between these compounds are not so distinctive, differences in plasma profile and CNS targeting were found. The maximum plasma concentration were attained at 18th min (tacrine; 38.20 ± 3.91 ng/ml and 7-MEOTA; 88.22 ± 15.19 ng/ml) after i.m. application in rats. Although the brain profiles seem to be similar; tacrine achieved 19.34 ± 0.71 ng/ml in 27 min and 7-MEOTA 15.80 ± 1.13 ng/ml in 22 min; the tacrine Kp (AUCbrain/AUCplasma) fit 1.20 and was significantly higher than 7-MEOTA Kp 0.10. Administration of tacrine and 7-MEOTA showed only mild elevation of some biochemical markers following single p.o. application in 24 hours and 7 days. Also histopathology revealed only mild-to-moderate changes following repeated p.o. administration for 14 days. It seems that small change in tacrine molecule leads to lower ability to penetrate through the biological barriers. The explanation that lower p.o. acute toxicity of 7-MEOTA depends only on differences in metabolic pathways may be now revised to newly described differences in pharmacokinetic and toxicological profiles.

Amaryllidaceae Alkaloids of Norbelladine-Type as Inspiration for Development of Highly Selective Butyrylcholinesterase Inhibitors: Synthesis, Biological Activity Evaluation, and Docking Studies.

Alzheimer's disease (AD) is a multifactorial neurodegenerative condition of the central nervous system (CNS) that is currently treated by cholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist, memantine. Emerging evidence strongly supports the relevance of targeting butyrylcholinesterase (BuChE) in the more advanced stages of AD. Within this study, we have generated a pilot series of compounds (1-20) structurally inspired from belladine-type Amaryllidaceae alkaloids, namely carltonine A and B, and evaluated their acetylcholinesterase (AChE) and BuChE inhibition properties. Some of the compounds exhibited intriguing inhibition activity for human BuChE (hBuChE), with a preference for BuChE over AChE. Seven compounds were found to possess a hBuChE inhibition profile, with IC50 values below 1 µM. The most potent one, compound 6, showed nanomolar range activity with an IC50 value of 72 nM and an excellent selectivity pattern over AChE, reaching a selectivity index of almost 1400. Compound 6 was further studied by enzyme kinetics, along with in-silico techniques, to reveal the mode of inhibition. The prediction of CNS availability estimates that all the compounds in this survey can pass through the blood-brain barrier (BBB), as disclosed by the BBB score.

Synthesis of New Biscoumarin Derivatives, In Vitro Cholinesterase Inhibition, Molecular Modelling and Antiproliferative Effect in A549 Human Lung Carcinoma Cells.

A series of novel C4-C7-tethered biscoumarin derivatives (12a-e) linked through piperazine moiety was designed, synthesized, and evaluated biological/therapeutic potential. Biscoumarin 12d was found to be the most effective inhibitor of both acetylcholinesterase (AChE, IC50 = 6.30 µM) and butyrylcholinesterase (BChE, IC50 = 49 µM). Detailed molecular modelling studies compared the accommodation of ensaculin (well-established coumarin derivative tested in phase I of clinical trials) and 12d in the human recombinant AChE (hAChE) active site. The ability of novel compounds to cross the blood-brain barrier (BBB) was predicted with a positive outcome for compound 12e. The antiproliferative effects of newly synthesized biscoumarin derivatives were tested in vitro on human lung carcinoma cell line (A549) and normal colon fibroblast cell line (CCD-18Co). The effect of derivatives on cell proliferation was evaluated by MTT assay, quantification of cell numbers and viability, colony-forming assay, analysis of cell cycle distribution and mitotic activity. Intracellular localization of used derivatives in A549 cells was confirmed by confocal microscopy. Derivatives 12d and 12e showed significant antiproliferative activity in A549 cancer cells without a significant effect on normal CCD-18Co cells. The inhibition of hAChE/human recombinant BChE (hBChE), the antiproliferative activity on cancer cells, and the ability to cross the BBB suggest the high potential of biscoumarin derivatives. Beside the treatment of cancer, 12e might be applicable against disorders such as schizophrenia, and 12d could serve future development as therapeutic agents in the prevention and/or treatment of Alzheimer's disease.

Structure Elucidation and Cholinesterase Inhibition Activity of Two New Minor Amaryllidaceae Alkaloids.

Two new minor Amaryllidaceae alkaloids were isolated from Hippeastrum × hybridum cv. Ferrari and Narcissus pseudonarcissus cv. Carlton. The chemical structures were identified by various spectroscopic (one- and two-dimensional (1D and 2D) NMR, circular dichroism (CD), high-resolution mass spectrometry (HRMS) and by comparison with literature data of similar compounds. Both isolated alkaloids were screened for their human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE) inhibition activity. One of the new compounds, a heterodimer alkaloid of narcikachnine-type, named narciabduliine (2), showed balanced inhibition potency for both studied enzymes, with IC50 values of 3.29 ± 0.73 µM for hAChE and 3.44 ± 0.02 µM for hBuChE. The accommodation of 2 into the active sites of respective enzymes was predicted using molecular modeling simulation.

Recent advances with 5-HT3 modulators for neuropsychiatric and gastrointestinal disorders.

Serotonin (5-hydroxytryptophan [5-HT]) is a biologically active amine expressed in platelets, in gastrointestinal (GI) cells and, to a lesser extent, in the central nervous system (CNS). This biogenic compound acts through the activation of seven 5-HT receptors (5-HT1-7 Rs). The 5-HT3 R is a ligand-gated ion channel belonging to the Cys-loop receptor family. There is a wide variety of 5-HT3 R modulators, but only receptor antagonists (known as setrons) have been used clinically for chemotherapy-induced nausea and vomiting and irritable bowel syndrome treatment. However, since the discovery of the setrons in the mid-1980s, a large number of studies have been published exploring new potential applications due their potency in the CNS and mild side effects. The results of these studies have revealed new potential applications, including the treatment of neuropsychiatric disorders such as schizophrenia, depression, anxiety, and drug abuse. In this review, we provide information related to therapeutic potential of 5-HT3 R antagonists on GI and neuropsychiatric disorders. The major attention is paid to the structure, function, and pharmacology of novel 5-HT3 R modulators developed over the past 10 years.

Aromatic Esters of the Crinane Amaryllidaceae Alkaloid Ambelline as Selective Inhibitors of Butyrylcholinesterase.

A total of 20 derivatives (1-20) of the crinane-type alkaloid ambelline were synthesized. These semisynthetic derivatives were assessed for their potency to inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). To predict central nervous system (CNS) availability, logBB was calculated, and the data correlated well with those obtained from the parallel artificial membrane permeability assay (PAMPA). All compounds should be able to permeate the blood-brain barrier (BBB) according to the obtained results. A total of 7 aromatic derivatives (5, 6, 7, 9, 10, 12, and 16) with different substitution patterns showed inhibitory potency against human serum BuChE (IC50 < 5 µM), highlighting the three top-ranked compounds as follows: 11-O-(1-naphthoyl)ambelline (16), 11-O-(2-methylbenzoyl)ambelline (6), and 11-O-(2-methoxybenzoyl)ambelline (9) with IC50 values of 0.10 ± 0.01, 0.28 ± 0.02, and 0.43 ± 0.04 µM, respectively. Notably, derivatives 6, 7, 9, and 16 displayed selective human BuChE (hBuChE) inhibition profiles with a selectivity index > 100. The in vitro results were supported by computational studies predicting plausible binding modes of the compounds in the active sites of hBuChE.