Benzothiadiazines derivatives as novel allosteric modulators of kainic acid receptors
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Benzothiadiazines derivatives as novel allosteric modulators of kainic acid receptors. / Puja, G.; Ravazzini, F.; Losi, G.; Bardoni, R.; Battisti, U. M.; Citti, C.; Cannazza, G.
In: Journal of Physiology and Pharmacology, Vol. 73, No. 1, 2022, p. 19-28.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Benzothiadiazines derivatives as novel allosteric modulators of kainic acid receptors
AU - Puja, G.
AU - Ravazzini, F.
AU - Losi, G.
AU - Bardoni, R.
AU - Battisti, U. M.
AU - Citti, C.
AU - Cannazza, G.
N1 - Publisher Copyright: © 2022, Polish Physiological Society. All rights reserved.
PY - 2022
Y1 - 2022
N2 - The majority of excitatory neurotransmission in vertebrate CNS is mediated by glutamate binding to different types of receptors. Among them, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and kainate receptors (KAR) are ionotropic receptors playing important pathophysiological roles. A number of small molecules acting as positive allosteric modulators (PAM) of AMPAR have been proposed as drugs for neurological disorders, however, there is no such abundance of ligands capable of modulating KARs activity. We investigated the ability of IDRA21 and of its derivative, compound 2 (c2), to modulate glutamate-evoked currents at native and recombinantly expressed AMPA and KA receptors. By using the patch clamp technique we analyzed the activity of the two compounds in primary cultures of cerebellar granule neurons and in HEK293 cells transiently transfected with KARs and AMPAR subunits. It resulted that both benzothiadiazine derivatives potentiate AMPAR and KAR mediated currents in native and recombinant receptors, c2 being always more potent and efficacious than IDRA21. The potency of both compounds was higher in native receptors than in recombinant receptors. In HEK293 cells transfected with AMPAR subunits, the efficacy of IDRA21 and c2 was much higher in GluA1 than in GluA2 homomeric receptors while their potency did not change. In recombinant KAR, both compounds had a potency in the high micromolar range, while the efficacy reached a maximum in the GluK2 expressing cells. The benzothiadiazine effect, both in native and recombinant receptors, was detected mainly on plateau current, involving a decrease in AMPAR and KAR desensitization. Our study demonstrates for the first time that two positive allosteric modulators of AMPAR, IDRA21 and its derivative, c2, potentiate KAR activity. Furthermore, we highlighted their subunit selectivity that may enable the design of potent and selective PAMs, which could be relevant for the development of new drugs and for a better understanding of KAR functions in the CNS.
AB - The majority of excitatory neurotransmission in vertebrate CNS is mediated by glutamate binding to different types of receptors. Among them, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and kainate receptors (KAR) are ionotropic receptors playing important pathophysiological roles. A number of small molecules acting as positive allosteric modulators (PAM) of AMPAR have been proposed as drugs for neurological disorders, however, there is no such abundance of ligands capable of modulating KARs activity. We investigated the ability of IDRA21 and of its derivative, compound 2 (c2), to modulate glutamate-evoked currents at native and recombinantly expressed AMPA and KA receptors. By using the patch clamp technique we analyzed the activity of the two compounds in primary cultures of cerebellar granule neurons and in HEK293 cells transiently transfected with KARs and AMPAR subunits. It resulted that both benzothiadiazine derivatives potentiate AMPAR and KAR mediated currents in native and recombinant receptors, c2 being always more potent and efficacious than IDRA21. The potency of both compounds was higher in native receptors than in recombinant receptors. In HEK293 cells transfected with AMPAR subunits, the efficacy of IDRA21 and c2 was much higher in GluA1 than in GluA2 homomeric receptors while their potency did not change. In recombinant KAR, both compounds had a potency in the high micromolar range, while the efficacy reached a maximum in the GluK2 expressing cells. The benzothiadiazine effect, both in native and recombinant receptors, was detected mainly on plateau current, involving a decrease in AMPAR and KAR desensitization. Our study demonstrates for the first time that two positive allosteric modulators of AMPAR, IDRA21 and its derivative, c2, potentiate KAR activity. Furthermore, we highlighted their subunit selectivity that may enable the design of potent and selective PAMs, which could be relevant for the development of new drugs and for a better understanding of KAR functions in the CNS.
KW - a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
KW - benzothiadiazines
KW - cell transfection
KW - cerebellar neurons
KW - HEK293 cells
KW - kainate receptor
KW - L-glutamate
KW - patch clamp
KW - synaptic modulation
U2 - 10.26402/jpp.2022.1.02
DO - 10.26402/jpp.2022.1.02
M3 - Journal article
C2 - 35639034
AN - SCOPUS:85131170927
VL - 73
SP - 19
EP - 28
JO - Journal of Physiology and Pharmacology
JF - Journal of Physiology and Pharmacology
SN - 0867-5910
IS - 1
ER -
ID: 344975188