Lindgren C

References (5)

Title : Structure-Activity Relationships Reveal Beneficial Selectivity Profiles of Inhibitors Targeting Acetylcholinesterase of Disease-Transmitting Mosquitoes - Vidal-Albalat_2023_J.Med.Chem__
Author(s) : Vidal-Albalat A , Kindahl T , Rajeshwari R , Lindgren C , Forsgren N , Kitur S , Tengo LS , Ekstrom F , Kamau L , Linusson A
Ref : Journal of Medicinal Chemistry , : , 2023
Abstract : Insecticide resistance jeopardizes the prevention of infectious diseases such as malaria and dengue fever by vector control of disease-transmitting mosquitoes. Effective new insecticidal compounds with minimal adverse effects on humans and the environment are therefore urgently needed. Here, we explore noncovalent inhibitors of the well-validated insecticidal target acetylcholinesterase (AChE) based on a 4-thiazolidinone scaffold. The 4-thiazolidinones inhibit AChE1 from the mosquitoes Anopheles gambiae and Aedes aegypti at low micromolar concentrations. Their selectivity depends primarily on the substitution pattern of the phenyl ring; halogen substituents have complex effects. The compounds also feature a pendant aliphatic amine that was important for activity; little variation of this group is tolerated. Molecular docking studies suggested that the tight selectivity profiles of these compounds are due to competition between two binding sites. Three 4-thiazolidinones tested for in vivo insecticidal activity had similar effects on disease-transmitting mosquitoes despite a 10-fold difference in their in vitro activity.
ESTHER : Vidal-Albalat_2023_J.Med.Chem__
PubMedSearch : Vidal-Albalat_2023_J.Med.Chem__
PubMedID: 37094110

Title : Broad-spectrum antidote discovery by untangling the reactivation mechanism of nerve agent inhibited acetylcholinesterase - Lindgren_2022_Chemistry_28_e202200678
Author(s) : Lindgren C , Forsgren N , Hoster N , Akfur C , Artursson E , Edvinsson L , Svensson R , Worek F , Ekstrom , Linusson A
Ref : Chemistry , 28 :e202200678 , 2022
Abstract : Reactivators are vital for the treatment of organophosphorus nerve agent (OPNA) intoxication but new alternatives are needed due to their limited clinical applicability. The toxicity of OPNAs stems from covalent inhibition of the essential enzyme acetylcholinesterase (AChE), which reactivators relieve via a chemical reaction with the inactivated enzyme. Here, we present new strategies and tools for developing reactivators. We discover suitable inhibitor scaffolds by using an activity-independent competition assay to study non-covalent interactions with OPNA-AChEs and transform these inhibitors into broad-spectrum reactivators. Moreover, we identify determinants of reactivation efficiency by analysing reactivation and prereactivation kinetics together with structural data. Our results show that new OPNA reactivators can be discovered rationally by exploiting detailed knowledge of the reactivation mechanism of OPNA-inhibited AChE.
ESTHER : Lindgren_2022_Chemistry_28_e202200678
PubMedSearch : Lindgren_2022_Chemistry_28_e202200678
PubMedID: 35420233
Gene_locus related to this paper: mouse-ACHE

Title : Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency - Knutsson_2018_J.Med.Chem_61_10545
Author(s) : Knutsson S , Engdahl C , Kumari R , Forsgren N , Lindgren C , Kindahl T , Kitur S , Wachira L , Kamau L , Ekstrom F , Linusson A
Ref : Journal of Medicinal Chemistry , 61 :10545 , 2018
Abstract : Resistance development in insects significantly threatens the important benefits obtained by insecticide usage in vector control of disease-transmitting insects. Discovery of new chemical entities with insecticidal activity is highly desired in order to develop new insecticide candidates. Here, we present the design, synthesis, and biological evaluation of phenoxyacetamide-based inhibitors of the essential enzyme acetylcholinesterase 1 (AChE1). AChE1 is a validated insecticide target to control mosquito vectors of, e.g., malaria, dengue, and Zika virus infections. The inhibitors combine a mosquito versus human AChE selectivity with a high potency also for the resistance-conferring mutation G122S; two properties that have proven challenging to combine in a single compound. Structure-activity relationship analyses and molecular dynamics simulations of inhibitor-protein complexes have provided insights that elucidate the molecular basis for these properties. We also show that the inhibitors demonstrate in vivo insecticidal activity on disease-transmitting mosquitoes. Our findings support the concept of noncovalent, selective, and resistance-breaking inhibitors of AChE1 as a promising approach for future insecticide development.
ESTHER : Knutsson_2018_J.Med.Chem_61_10545
PubMedSearch : Knutsson_2018_J.Med.Chem_61_10545
PubMedID: 30339371
Gene_locus related to this paper: mouse-ACHE

Title : Benefits of statistical molecular design, covariance analysis, and reference models in QSAR: a case study on acetylcholinesterase - Andersson_2015_J.Comput.Aided.Mol.Des_29_199
Author(s) : Andersson CD , Hillgren JM , Lindgren C , Qian W , Akfur C , Berg L , Ekstrom F , Linusson A
Ref : J Comput Aided Mol Des , 29 :199 , 2015
Abstract : Scientific disciplines such as medicinal- and environmental chemistry, pharmacology, and toxicology deal with the questions related to the effects small organic compounds exhort on biological targets and the compounds' physicochemical properties responsible for these effects. A common strategy in this endeavor is to establish structure-activity relationships (SARs). The aim of this work was to illustrate benefits of performing a statistical molecular design (SMD) and proper statistical analysis of the molecules' properties before SAR and quantitative structure-activity relationship (QSAR) analysis. Our SMD followed by synthesis yielded a set of inhibitors of the enzyme acetylcholinesterase (AChE) that had very few inherent dependencies between the substructures in the molecules. If such dependencies exist, they cause severe errors in SAR interpretation and predictions by QSAR-models, and leave a set of molecules less suitable for future decision-making. In our study, SAR- and QSAR models could show which molecular sub-structures and physicochemical features that were advantageous for the AChE inhibition. Finally, the QSAR model was used for the prediction of the inhibition of AChE by an external prediction set of molecules. The accuracy of these predictions was asserted by statistical significance tests and by comparisons to simple but relevant reference models.
ESTHER : Andersson_2015_J.Comput.Aided.Mol.Des_29_199
PubMedSearch : Andersson_2015_J.Comput.Aided.Mol.Des_29_199
PubMedID: 25351962

Title : Endocannabinoids mediate muscarine-induced synaptic depression at the vertebrate neuromuscular junction - Newman_2007_Eur.J.Neurosci_25_1619
Author(s) : Newman Z , Malik P , Wu TY , Ochoa C , Watsa N , Lindgren C
Ref : European Journal of Neuroscience , 25 :1619 , 2007
Abstract : Endocannabinoids (eCBs) inhibit neurotransmitter release throughout the central nervous system. Using the Ceratomandibularis muscle from the lizard Anolis carolinensis we asked whether eCBs play a similar role at the vertebrate neuromuscular junction. We report here that the CB(1) cannabinoid receptor is concentrated on motor terminals and that eCBs mediate the inhibition of neurotransmitter release induced by the activation of M(3) muscarinic acetylcholine (ACh) receptors. N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3 -carboxamide, a CB(1) antagonist, prevents muscarine from inhibiting release and arachidonylcyclopropylamide (ACPA), a CB(1) receptor agonist, mimics M(3) activation and occludes the effect of muscarine. As for its mechanism of action, ACPA reduces the action-potential-evoked calcium transient in the nerve terminal and this decrease is more than sufficient to account for the observed inhibition of neurotransmitter release. Similar to muscarine, the inhibition of synaptic transmission by ACPA requires nitric oxide, acting via the synthesis of cGMP and the activation of cGMP-dependent protein kinase. 2-Arachidonoylglycerol (2-AG) is responsible for the majority of the effects of eCB as inhibitors of phospholipase C and diacylglycerol lipase, two enzymes responsible for synthesis of 2-AG, significantly limit muscarine-induced inhibition of neurotransmitter release. Lastly, the injection of (5Z,8Z,11Z,14Z)-N-(4-hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide (an inhibitor of eCB transport) into the muscle prevents muscarine, but not ACPA, from inhibiting ACh release. These results collectively lead to a model of the vertebrate neuromuscular junction whereby 2-AG mediates the muscarine-induced inhibition of ACh release. To demonstrate the physiological relevance of this model we show that the CB(1) antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3 -carboxamide prevents synaptic inhibition induced by 20 min of 1-Hz stimulation.
ESTHER : Newman_2007_Eur.J.Neurosci_25_1619
PubMedSearch : Newman_2007_Eur.J.Neurosci_25_1619
PubMedID: 17408433