Poster (Scientific congresses and symposiums)
Advances in Targeting Kainic Acid Receptors: Developing Selective Positive Allosteric Modulators from the 1,2,4-Benzothiadiazine 1,1-Dioxide scaffold
Colson, Thomas; Piette, Marine; Bay, Y. et al.
2024CIRM Day 2024
Editorial reviewed
 

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Keywords :
Kainate Receptors; PAM; Positive; Allosteric; Modulators; Alzheimer; psychological disorders; KAR; AMPA; glutamate; BPAM344; BPAM121; BPAM521; IDRA-21; 1,2,4-benzothiadiazine 1,1-dioxides; GluK1; LBD; Modulation; GluA2; Crystalisation; AMT2_21; MedChem2023; Friedel Craft
Abstract :
[en] Due to glutamate's crucial role in brain function, there is a considerable interest in the development of therapeutics targeting specific glutamatergic receptors. Among these, positive allosteric modulators (PAMs) of AMPA receptors (AMPArPams) and more recently, kainate receptors (KArPams), have drawn significant attention. In particular, the latter appears to reduce the excitability of glutamatergic pathways, contributing to neuronal stability. Over the past two decades in our laboratory, extensive effort has focused on developing and synthesizing numerous original compounds from the 1,2,4-benzothiadiazine 1,1-dioxide class and related analogues. Some of these compounds demonstrated potent activity as positive allosteric modulators of AMPA receptors, from which BPAM344 being a notable example. Progress in structural analysis provided insights into kainic acid receptors (KArs), particularly regarding the allosteric binding site within the receptor's ligand-binding domain (LBD). Recent research revealed that certain compounds developed in our lab, including BPAM344, also exhibited positive allosteric modulation of KArs. Further investigations highlighted that specific substitution of the benzothiadiazine structure enhanced positive allosteric modulation of KArs. These findings guided the design of a new series of benzothiadiazine dioxides, building upon initial observations with BPAM344 and related structures. This facilitated a deeper understanding of how these molecules interact with KArs' binding domains. Our ongoing investigations, including molecular modeling, aim to develop compounds effectively occupying the receptor's allosteric pocket. We're also striving to obtain modulators with selectivity for either the GluK1-3 or GluK4-5 subunits of KArs.
Research center :
CIRM - Centre Interdisciplinaire de Recherche sur le Médicament - ULiège [BE]
Disciplines :
Pharmacy, pharmacology & toxicology
Chemistry
Author, co-author :
Colson, Thomas  ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Piette, Marine ;  Université de Liège - ULiège > Faculté de Médecine > Master sc. pharma., fin. spéc. conc. & dév. méd. - bioana.
Bay, Y.;  Copenhagen University Hospital [DK] > Department of Drug Design and Pharmacology > Molecular and Cellular Pharmacology
Pickering, D.S.;  Copenhagen University Hospital [DK] > Department of Drug Design and Pharmacology > Molecular and Cellular Pharmacology
Kristensen, A.S.;  Copenhagen University Hospital [DK] > Department of Drug Design and Pharmacology > Molecular and Cellular Pharmacology
Baudino, Giacomo ;  Université de Liège - ULiège > Faculté de Médecine > Master sc. pharma., fin. spéc. conc. & dév. méd. - bioana.
Tchekounang Tchonwa, Indrid Fallane ;  Université de Liège - ULiège > Faculté des Sciences > Master en sc. chimiques, fin. did.
Pochet, Lionel;  UNamur - University of Namur [BE] > Namur Medicine & Drug Innovation Center (NAMEDIC - NARILIS)
Goffin, Eric ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Lesenfants, Cindy  ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Kastrup, J.S.;  Copenhagen University Hospital [DK] > Department of Drug Design and Pharmacology > Biostructural Research
Pirotte, Bernard ;  Université de Liège - ULiège > Département de pharmacie ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Francotte, Pierre  ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM) ; Université de Liège - ULiège > Département de pharmacie
More authors (3 more) Less
Language :
English
Title :
Advances in Targeting Kainic Acid Receptors: Developing Selective Positive Allosteric Modulators from the 1,2,4-Benzothiadiazine 1,1-Dioxide scaffold
Publication date :
31 January 2024
Event name :
CIRM Day 2024
Event place :
Liège, Belgium
Event date :
31/01/2024
Peer reviewed :
Editorial reviewed
Funders :
F.R.S.-FNRS - Fund for Scientific Research [BE]
Leon Fredericq Foundation [BE]
Available on ORBi :
since 01 February 2024

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