Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Highly efficient acetylcholinesterase (AChE) and serotonin transporter (SERT) dual inhibitors, (S)-4 and (R)-13 were designed and synthesized on the basis of the hypothetical model of AChE active site. Both compounds showed potent inhibitory activities against AChE and SERT. [structure: see text]
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PMID:Design and synthesis of dual inhibitors of acetylcholinesterase and serotonin transporter targeting potential agents for Alzheimer's disease. 1232 18

We have designed and synthesized a dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT) as a novel class of treatment drugs for Alzheimer's disease on the basis of a hypothetical model of the AChE active site. Dual inhibitions of AChE and SERT would bring about greater therapeutic effects than AChE inhibition alone and avoid adverse peripheral effects caused by excessive AChE inhibition. Compound (S)-6j exhibited potent inhibitory activities against AChE (IC(50)=101 nM) and SERT (IC(50)=42 nM). Furthermore, (S)-6j showed inhibitory activities of both AChE and SERT in mice brain following oral administration.
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PMID:Design, synthesis and structure-activity relationships of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease. 1267 Jun 45

Alzheimer's disease (AD) has been treated with acetylcholinesterase (AChE) inhibitors such as donepezil. However, the clinical usefulness of AChE inhibitors is limited mainly due to their adverse peripheral effects. Depression seen in AD patients has been treated with serotonin transporter (SERT) inhibitors. We considered that combining SERT and AChE inhibition could improve the clinical usefulness of AChE inhibitors. In a previous paper, we found a potential dual inhibitor, 1, of AChE (IC50=101 nM) and SERT (IC50=42 nM), but its AChE inhibition activity was less than donepezil (IC50=10 nM). Here, we report the conformationally restricted (R)-18a considerably enhanced inhibitory activity against AChE (IC50=14 nM) and SERT (IC50=6 nM).
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PMID:A conformational restriction approach to the development of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease. 1312 77

A dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT), RS-1259 (4-[1S)-methylamino-3-(4-nitrophenoxy)]propylphenyl N,N-dimethylcarbamate (fumaric acid)(1/2)salt), was newly synthesized. RS-1259 simultaneously inhibited AChE and SERT in the brain following an oral administration in mice and rats. Actual simultaneous elevation of extracellular levels of 5-HT and ACh in the rat hippocampus was confirmed by microdialysis. The compound was as effective as SERT inhibitors such as fluoxetine and fluvoxamine in a 5-hydroxytryptophan-enhancing test in mice. Spatial memory deficits in the two-platform task of a water maze in aged rats were ameliorated by RS-1259 as well as donepezil. Both RS-1259 and donepezil increased the awake episodes in the daytime electroencephalogram of rats. Although RS-1259 was weaker than donepezil in enhancing central cholinergic transmission, as observed by ACh elevation in the hippocampus and memory enhancement in aged rats, the efficacy of RS-1259 on the consciousness level, which reflects the whole activity in the brain, was almost the same as that of donepezil. These results suggest that both cholinergic and serotonergic systems are involved in maintaining brain arousal and that a dual inhibitor of AChE and SERT may be useful for the treatment of cognitive disorders associated with reduced brain activity such as in Alzheimer's disease.
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PMID:Pharmacological characterization of RS-1259, an orally active dual inhibitor of acetylcholinesterase and serotonin transporter, in rodents: possible treatment of Alzheimer's disease. 1450 Nov 58

In the recent decades the use of traditional medicine in Lebanon has increased. Aqueous, ethanol and ethyl acetate extracts of seven Lebanese plants that are used traditionally for neurological disorders as Alzheimer's disease, epilepsy and affective disorders as depression were tested for inhibition of acetylcholinesterase and affinity to the GABA(A)-benzodiazepine site and to the serotonin transporter. Ethyl acetate extracts of Salvia triloba, Lavandula officinalis, Origanum syriacum and Artemisia herba-alba exhibited weak activity in the acetylcholinesterase assay. None of the plants were active in the serotonin transporter assay. An ethanolic extract of Artemisia herba-alba had good affinity to the GABA(A)-benzodiazepine receptor site; ethanolic extracts of Melissa officinalis and Salvia triloba had moderate activity.
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PMID:Screening of traditionally used Lebanese herbs for neurological activities. 1565 88

The centrifugal systems innervating the olfactory bulb are important elements in the functional regulation of the olfactory pathway. In this study, the selective innervation of specific glomeruli by serotonergic, noradrenergic and cholinergic centrifugal axons was analyzed. Thus, the morphology, distribution and density of positive axons were studied in the glomerular layer of the main olfactory bulb of the rat, using serotonin-, serotonin transporter- and dopamine-beta-hydroxylase-immunohistochemistry and acetylcholinesterase histochemistry in serial sections. Serotonin-, serotonin transporter-immunostaining and acetylcholinesterase-staining revealed a higher heterogeneity in the glomerular layer of the main olfactory bulb than previously reported. In this sense, four types of glomeruli could be identified according to their serotonergic innervation. The main distinctive feature of these four types of glomeruli was their serotonergic fibre density, although they also differed in their size, morphology and relative position throughout the rostro-caudal main olfactory bulb. In this sense, some specific regions of the glomerular layer were occupied by glomeruli with a particular morphology and a characteristic serotonergic innervation pattern that was consistent from animal to animal. Regarding the cholinergic system, we offer a new subclassification of glomeruli based on the distribution of cholinergic fibres in the glomerular structure. Finally, the serotonergic and cholinergic innervation patterns were compared in the glomerular layer. Sexual differences concerning the density of serotonergic fibres were observed in the atypical glomeruli (characterized by their strong cholinergic innervation). The present report provides new data on the heterogeneity of the centrifugal innervation of the glomerular layer that constitutes the morphological substrate supporting the existence of differential modulatory levels among the entire glomerular population.
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PMID:Heterogeneous targeting of centrifugal inputs to the glomerular layer of the main olfactory bulb. 1592 86

To elucidate the organization of the serotoninergic innervation within the orbitofrontal cortex (OFC), serotonin transporter (SERT) density was quantified by autoradiography using [(3)H]cyanoimipramine binding. In six adult vervet monkeys, 15 architectonic areas were delineated according to cytoarchitectonic (Nissl), myeloarchitectonic (Gallyas) and chemoarchitectonic (acetylcholinesterase) criteria to assess SERT distribution at two levels of organization: cortical area and cortical type. For cortical type, the 15 areas were evenly divided into three different categories primarily based upon the degree of granularization of layer IV: agranular, dysgranular, and granular. Within agranular and dysgranular, but not granular cortical types, SERT density was area-specific and progressively decreased in a medial to lateral gradient. Across cortical types, SERT density decreased in a caudal to rostral gradient: agranular>dysgranular>granular. A similar caudal to rostral gradient was seen when serotonin content was measured (using high performance liquid chromatography) in areas representative of each cortical type. Collectively, these results suggest that the serotoninergic innervation is organized according to both cortical type and area, and is thus structured to differentially modulate information processing within the OFC.
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PMID:Architectonic distribution of the serotonin transporter within the orbitofrontal cortex of the vervet monkey. 1776 46

The serotonin transporter protein (SERT) has been the target for the development of several modern antidepressants with an objective of achieving selectivity over other monoamine transporters, thereby minimising side effects observed in the older generation of tricyclic antidepressants. The clinical selective serotonin reuptake inhibitors (SSRIs) have been shown to be among the most effective therapies in the treatment of depression. However they have clinical disadvantages over other classes of antidepressant drugs such as slow onset of action nausea and sleep disruption. The negative feedback loop attributed to the presynaptic 5-HT(1A) receptors has been implicated in the "time lag" observed in many patients between the administration of the SSRI and its observed therapeutic action. In recent years the focus has been on developing compounds with dual affinity for serotonergic auto-receptors along with an inhibitory activity at SERT. These structurally diverse products promise to be the next generation of anti-depressant medicines. This review presents an analysis of the recently reported structural classes with SSRI activity and rationalises the unique relationship between their molecular properties and biological activities. Specific emphasis is placed on the development of molecular structures with dual serotonergic activity. Recent advances in the design and synthesis of single molecular entities possessing 5-HT reuptake inhibition together with 5-HT(1A), 5-HT(1B), 5-HT(1D), 5-HT(2A), DAT, NET, alpha (2)-adrenoceptor and acetylcholinesterase antagonism are reviewed. The structural studies to identify proposed SERT binding sites together with the role of structure and ligand based design in the development of more effective SSRIs are summarised.
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PMID:Recent developments in the design of anti-depressive therapies: targeting the serotonin transporter. 1867 23

The majority of the population in South Africa use traditional health care to treat various mental conditions. In this review, we present ethnobotanical information on plants used by the traditional healers in South Africa to treat mental illnesses, specifically epilepsy, depression, age-related dementia and debilitative mental disorders. Details of the recent scientific studies conducted on some of these plants are reviewed. Extracts of Searsia chirindensis, Cotelydon orbiculata and Leonotis leonurus have shown in vivo anticonvulsant activity. Extracts from Searsia dentata and Searsia pyroides showed spontaneous epileptiform discharge in mouse cortical slices, and acted as NMDA-receptor antagonists. Apigenin, amentoflavone and agathisflavone with affinity to the benzodiazepine site on the GABA(A)-receptor were isolated from Searsia pyroides. Naringenin with affinity to the GABA(A)-benzodiazepine receptor was isolated from Mentha aquatica. Agapanthus campanulatus, Boophone disticha, Mondia whitei and Xysmalobium undulatum exhibited antidepressant-like activity in three in vivo models for depression. Amaryllidaceae alkaloids with activity to the serotonin transporter were isolated from Boophone disticha. The alkaloid mesembrine, which act as a serotonin reuptake inhibitor, was isolated from Sceletium tortuosum. Investigations of plants used to treat age-related dementia and debilitative mental disorders lead to the isolation of a number of Amaryllidaceae alkaloids with acetylcholinesterase inhibitory activity from Boophone disticha and Crinum species. Extracts of Mentha aquatica, Gasteria croucheri, Ruta graveolens and Scotia brachypetala inhibited MAO-B. Naringenin was isolated from Mentha aquatica as a MAO inhibitor. Only a small number of the more than 300 southern African plant species reported to treat or affect the CNS have been scientifically evaluated. Very few of the active compounds have been isolated and identified.
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PMID:Review on plants with CNS-effects used in traditional South African medicine against mental diseases. 1877 71

To date, acetylcholinesterase (AChE) inhibitors have been clinically effective drugs for the palliative treatment of Alzheimer's disease, but their clinical efficacy is limited, mainly due to their adverse effects on peripheral organs. Since patients of Alzheimer's disease often exhibit depression as well as memory impairment, dual inhibitors of AChE and serotonin transporter (SERT) would be a better therapeutic method. Anti-depressive effects based on SERT inhibition would reduce the dose-related side effects of AChE inhibitors. Such dual inhibitors were designed by the hybridization of rivastigmine and fluoxetine based on a hypothetical model of the AChE active site. Various derivatives were synthesized and evaluated for their in vitro inhibition, and then (S)-5j (RS-1259), which possessed balanced inhibitory activities of AChE (IC(50)=101 nM) and SERT (IC(50)=42 nM), was successfully obtained. An ex vivo experiment in mice indicated that (S)-5j (RS-1259) simultaneously inhibited AChE and SERT in the brain following an oral administration. The simultaneous elevation of extracellular levels of acetylcholine and serotonin in the rat hippocampus was actually confirmed by microdialysis.
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PMID:Development of an efficient therapeutic agent for Alzheimer's disease: design and synthesis of dual inhibitors of acetylcholinesterase and serotonin transporter. 2019 Apr 29


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