Synthesis and characterization of novel metabotropic glutamate receptor 2/3 (mGluR2/3) positive...
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Synthesis and characterization of novel metabotropic glutamate receptor 2/3 (mGluR 2/3 ) positive allosteric modulator (PAM) Piotr Brañski 1 *, Jakub Staroñ 2 , Ryszard Bugno 2 , Joanna Wieroñska 1 , Andrzej Bojarski 2 , Grzegorz Burnat, Agnieszka Pa³ucha-Poniewiera 1 , Andrzej Pilc 1 Background: Glutamate is the major excitatory neu- rotransmitter in the central nervous system. Its effects are modulated by both ionotropic and metabotropic glutamate receptors (mGluRs). The Group II mGluRs are highly expressed in the cerebral cortex, hippocam- pus, striatum, amygdala, frontal cortex and nucleus accumbens. MGluR and mGluR are found predomi- nantly presynaptically but outside of the active zone of glutamate release, where they largely function to regulate neurotransmitter release via coupling to G -associated signal transduction cascades and through ion channel regulation via G subunit activ- ity. Specific for Class C GPCRs, to which mGlu re- ceptors belong, is their large N-terminal extracellular domain, where the endogenous agonist binds. Ligands can bind the orthosteric, endogenous agonist, binding site or an allosteric domain which is located in the transmembrane region. A lack of success in developing highly subtype- selective agonists and antagonists that act at the or- thosteric glutamate binding site has led to the devel- opment of a novel approach to the activation of mGlu using highly selective positive allosteric modulators (PAMs) of this receptor. As opposed to di- rect activation of mGlu PAMs dramatically potenti- ate the response of the receptor to its endogenous ligand glutamate by interaction with transmembrane region of mGlu receptors. Group II metabotropic glutamate receptors have shown activity in a range of preclinical animal models of anxiety schizophrenia and addiction. Aim: Identification novel chemical scaffold possess- ing mGluR positive allosteric modulation activity. Methods: The screening study and activity of po- tential PAM was determined using [ S]-GTPgS assay. Results: Via screening of in-house compound col- lection we have identified novel chemical scaffold possessing mGluR PAM activity. Series of 28 compounds have been designed, syn- thesized, and characterized. The SKS-11d compound induced a leftward-shift of the glutamate concentration-response curve. None of compounds did interact with mGluR and mGluR receptors up to 30 μM. Compound SKS-11d was active in SIH and four plate test in mice. Conclusions: Compound SKS-11d is a novel posi- tive allosteric modulator of mGlu2/3 receptors. Acknowledgments: Validation of HEK-293 cell line as a molecular tool for pharmacological study of mGluR 7 receptor Grzegorz Burnat*, Piotr Brañski, Paulina Chorobik, Barbara Chruœcicka, Andrzej Pilc Background: mGluR is a very promising target re- ceptor for psychopharmacological research and phar- macological industry. It is suggested potential role the mGluR in the pathophysiology of schizophrenia, 577 The Twentieth Days of Neuropsychopharmacology
Transcript of Synthesis and characterization of novel metabotropic glutamate receptor 2/3 (mGluR2/3) positive...
Synthesis and characterization of novel metabotropic glutamatereceptor 2/3 (mGluR2/3) positive allosteric modulator (PAM)Piotr Brañski1*, Jakub Staroñ2, Ryszard Bugno2, Joanna Wieroñska1, Andrzej Bojarski2,Grzegorz Burnat, Agnieszka Pa³ucha-Poniewiera1, Andrzej Pilc1
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Background: Glutamate is the major excitatory neu-rotransmitter in the central nervous system. Its effectsare modulated by both ionotropic and metabotropicglutamate receptors (mGluRs). The Group II mGluRsare highly expressed in the cerebral cortex, hippocam-pus, striatum, amygdala, frontal cortex and nucleusaccumbens. MGluR� and mGluR� are found predomi-nantly presynaptically but outside of the active zoneof glutamate release, where they largely function toregulate neurotransmitter release via coupling toG����-associated signal transduction cascades andthrough ion channel regulation via G�� subunit activ-ity. Specific for Class C GPCRs, to which mGlu��� re-ceptors belong, is their large N-terminal extracellulardomain, where the endogenous agonist binds. Ligandscan bind the orthosteric, endogenous agonist, bindingsite or an allosteric domain which is located in thetransmembrane region.A lack of success in developing highly subtype-
selective agonists and antagonists that act at the or-thosteric glutamate binding site has led to the devel-opment of a novel approach to the activation ofmGlu��� using highly selective positive allostericmodulators (PAMs) of this receptor. As opposed to di-rect activation of mGlu��� PAMs dramatically potenti-ate the response of the receptor to its endogenous
ligand glutamate by interaction with transmembraneregion of mGlu��� receptors.Group II metabotropic glutamate receptors have
shown activity in a range of preclinical animal modelsof anxiety schizophrenia and addiction.
Aim: Identification novel chemical scaffold possess-ing mGluR��� positive allosteric modulation activity.
Methods: The screening study and activity of po-tential PAM was determined using [��S]-GTP�S assay.
Results: Via screening of in-house compound col-lection we have identified novel chemical scaffoldpossessing mGluR��� PAM activity.Series of 28 compounds have been designed, syn-
thesized, and characterized.The SKS-11d compound induced a leftward-shift
of the glutamate concentration-response curve.None of compounds did interact with mGluR� and
mGluR� receptors up to 30 μM.Compound SKS-11d was active in SIH and four
plate test in mice.Conclusions: Compound SKS-11d is a novel posi-
tive allosteric modulator of mGlu2/3 receptors.
Acknowledgments:
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Validation of HEK-293 cell line as a molecular toolfor pharmacological study of mGluR7 receptorGrzegorz Burnat*, Piotr Brañski, Paulina Chorobik, Barbara Chruœcicka, Andrzej Pilc
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Background: mGluR� is a very promising target re-ceptor for psychopharmacological research and phar-
macological industry. It is suggested potential role themGluR� in the pathophysiology of schizophrenia,
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The Twentieth Days of Neuropsychopharmacology���� ���������
