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Jeffrey P Conn – One of the best experts on this subject based on the ideXlab platform.

  • structure of a class c gpcr metabotropic glutamate receptor 1 bound to an Allosteric Modulator
    Science, 2014
    Co-Authors: Huixian Wu, Chong Wang, Karen J Gregory, Colleen M Niswender, Vsevolod Katritch, Jens Meiler, Vadim Cherezov, Jeffrey P Conn, Raymond C Stevens
    Abstract:

    The excitatory neurotransmitter glutamate induces Modulatory actions via the metabotropic glutamate receptors (mGlus), which are class C G protprotein-coupled receptors (GPCRs). We determined the 2.8 A resolution structure of the human mGlu1 receptor seven-transmembrane (7TM) domain bound to a negative Allosteric Modulator FITM. The Modulator binding site partially overlaps with the orthosteric binding sites of class A GPCRs, but is more restricted compared to most other GPCRs. We observed a parallel 7TM dimer, mediated by cholesterols, suggesting that signaling initiated by glutamate’s interaction with the extracellular domain might be mediated via 7TM interactions within the full-length receptor dimer. A combination of crystallography, structure-activity relationships, mutagenesis, and full-length dimer modeling provides insights on the Allosteric modulation and activation mechanism of class C GPCRs.

  • chemical lead optimization of a pan gq machr m1 m3 m5 positive Allosteric Modulator pam lead part i development of the first highly selective m5 pam
    Bioorganic & Medicinal Chemistry Letters, 2010
    Co-Authors: Thomas M Bridges, Jeffrey P Conn, Patrick R Gentry, Hyekyung P Cho, Phillip J Kennedy, Micah L Breininger, Corey R Hopkins, Craig W Lindsley
    Abstract:

    This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M(5)-preferring positive Allosteric Modulator (PAM), discovered through analog work around VU0119498, a pan G(q) mAChR M(1), M(3), M(5) PAM. An iterative library synthesis approach delivered the first selective M(5) PAM (no activity at M(1)-M(4) @ 30microM), and an important tool compound to study the role of M(5) in the CNS.

  • synthesis and sar of a novel positive Allosteric Modulator pam of the metabotropic glutamate receptor 4 mglur4
    Bioorganic & Medicinal Chemistry Letters, 2009
    Co-Authors: Richard Williams, Colleen M Niswender, Jeffrey P Conn, Kari A Johnson, Patrick R Gentry, Charles David Weaver
    Abstract:

    This Letter describes the synthesis and SAR of the novel positive Allosteric Modulator, VU0155041, a compound that has shown in vivo efficacy in rodent models of Parkinson‘s disease. The synthesis takes advantage of an iterative parallel synthesis approach to rapidly synthesize and evaluate a number of analogs of VU0155041.

Thomas M Bridges – One of the best experts on this subject based on the ideXlab platform.

  • Antipsychotic Drug-Like Effects of the Selective M_4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100
    Neuropsychopharmacology, 2014
    Co-Authors: Nellie E Byun, Michael Grannan, Michael Bubser, Robert L Barry, Analisa Thompson, John Rosanelli, Raajaram Gowrishankar, Nathaniel D Kelm, Stephen Damon, Thomas M Bridges
    Abstract:

    Accumulating evidence suggests that selective M_4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M_4 activators were unsuccessful because of the lack of M_4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M_4 positive Allosteric Modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M_4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M_4-mediated modulation of the amphetamine response included the nucleus accumbens (NAS), caudate-putamen (CP), hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M_4 modulation of amphetamine-induced brain activation, including the NAS and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in NAS and CP. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M_4 PAMs as a new approach to the treatment of psychosis and cognitive impairments associated with psychiatric disorders such as schizophrenia.

  • effects of the m4 muscarinic receptor positive Allosteric Modulator vu0467154 on cognition and pyramidal cell firing properties in layer v of the mpfc 845 9
    The FASEB Journal, 2014
    Co-Authors: Michael Grannan, Colleen M Niswender, Mark E Duggan, Thomas M Bridges, Michael Bubser, Robert W Gould, Ditte Dencker Thorbek, J S Daniels, Meredith J Noetzel, Nicholas J Brandon
    Abstract:

    Many symptoms in schizophrenia are attributed to alternations in normal glutamatergic signaling in the prefrontal cortex (PFC). In preclinical studies, psychotomimetic agents like the N-methyl-D-aspartate receptor antagonist MK-801 induce enhanced spontaneous firing at glutamatergic synapses within the medial PFC and cognitive impairments. Recently, we reported the discovery of VU0467154, an optimized positive Allosteric Modulator (PAMs) of the M4 muscarinic acetylcholine receptor with low nanomolar potency in vitro and suitable pharmacokinetic properties for in vivo studies. Here we evaluated the ability of VU0467154 to reverse alterations in mPFC signaling and behavioral deficits induced by MK-801. In vivo electrophysiology studies in anesthetized rats revealed that pretreatment with VU0467154 reversed MK-801-induced changes in firing rates in layer V pyramidal cells of the mPFC, while having no effect on firing rates when administered alone. Moreover, VU0467154 produced dose-related reversals of MK-801…

  • discovery of a selective m4 positive Allosteric Modulator based on the 3 amino thieno 2 3 b pyridine 2 carboxamide scaffold development of ml253 a potent and brain penetrant compound that is active in a preclinical model of schizophrenia
    Bioorganic & Medicinal Chemistry Letters, 2013
    Co-Authors: Thomas M Bridges, Bruce J Melancon, Atin Lamsal, Paige N Vinson, Thomas J Utley
    Abstract:

    Abstract Herein we report a next generation muscarinic receptor 4 (M4) positive Allosteric Modulator (PAM), ML253 which exhibits nanomolar activity at both the human (EC50 = 56 nM) and rat (EC50 = 176 nM) receptors and excellent efficacy by the left-ward shift of the ACh concentration response curve (fold shift, human = 106; rat = 50). In addition, ML253 is selective against the four other muscarinic subtypes, displays excellent CNS exposure and is active in an amphetamine-induced hyperlocomotion assay.

Jeanphilippe Pin – One of the best experts on this subject based on the ideXlab platform.

  • a negative Allosteric Modulator modulates gabab receptor signalling through gb2 subunits
    Biochemical Journal, 2016
    Co-Authors: Bing Sun, Jeanphilippe Pin, Linhai Chen, Lei Liu, Zhixiong Xia, Fajun Nan, Jianfeng Liu
    Abstract:

    An γ-aminobutyric acid type B (GABA B )-receptor mediates slow and prolonged synaptic inhibition in the central nervous system, which represents an interesting target for the treatment of various diseases and disorders of the central nervous system. To date, only one activator of the GABA B -receptor, baclofen, is on the market for the treatment of spasticity. Inhibitors of the GABA B -receptor, such as antagonists, show anti-absence seizure activity and pro-cognitive properties. In a search for Allosteric compounds of the GABA B -receptor, although several positive Allosteric Modulators have been developed, it is only recently that the first negative Allosteric Modulator (NAM), CLH304a (also named Compound 14), has been reported. In the present study, we provide further information on the mechanism of action of CLH304a, and also show the possibility of designing more NAMs, such as CLH391 and CLH393, based on the structure of CLH304a. First we show that CLH304a inhibits native GABA B -receptor activity in cultured cerebellar granular neurons. We then show that CLH304a has inverse agonist properties and non-competitively inhibits the effect of agonists, indicating that it binds at a different site to GABA. The GABA B -receptor is a mandatory heterodimer made of GB1 subunits, in which agonists bind, and GB2 subunits, which activate G-proteins. By using various combinations made up of wild-type and/or mutated GB1 and GB2 subunits, we show that CLH304a acts on the heptahelical domain of GB2 subunits. These data revealed the possibility of designing innovative NAMs acting in the heptahelical domain of the GB2 subunits, offering novel possibilities for therapeutic intervention based on GABA B -receptor inhibition.

  • an Allosteric Modulator to control endogenous g protein coupled receptors with light
    Nature Chemical Biology, 2014
    Co-Authors: Silvia Pittolo, Kay Eckelt, Xavier Rovira, Cyril Goudet, Artur Llobet, Jesús Giraldo, Xavier Gomezsantacana, James A R Dalton, Jeanphilippe Pin, Amadeu Llebaria
    Abstract:

    Controlling drug activity with light offers the possibility of enhancing pharmacological selectivity with spatial and temporal regulation, thus enabling highly localized therapeutic effects and precise dosing patterns. Here we report on the development and characterization of what is to our knowledge the first photoswitchable Allosteric Modulator of a G protprotein-coupled receptor. Alloswitch-1 is selective for the metabotropic glutglutamateeptor mGlu5 and enables the optical control of endogenous mGlu5 receptors.

  • n 4 chloro 2 1 3 dioxo 1 3 dihydro 2h isoindol 2 yl methyl phenyl 2 hydroxybenzamide cppha acts through a novel site as a positive Allosteric Modulator of group 1 metabotropic glutamate receptors
    Molecular Pharmacology, 2008
    Co-Authors: Yelin Chen, Jeanphilippe Pin, Cyril Goudet, Jeffrey P Conn
    Abstract:

    Recent studies suggest that a novel positive Allosteric Modulator (PAM) of the metabotropic glutglutamateeptor (mGluRs), mGluR5, termed 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (VU-29), potentiates mGluR5 responses by actions at a site that is overlapping with the binding site of 2-methyl-6-(phenylethynyl)pyridine (MPEP), a previously identified negative Allosteric Modulator of this receptor. It is interesting that a structurally distinct PAM, N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA), does not to bind to the MPEP site. We now report that CPPHA potentiates mGluR5 responses by a mechanism that is distinct from that of VU-29. VU-29- and CPPHA-induced potentiation of mGluR5 responses are blocked by a neutral ligand at the MPEP Allosteric site termed 5-methyl-2-(phenylethynyl)pyridine (5MPEP). However, increasing concentrations of 5MPEP induce parallel rightward shifts in the VU-29 concentration-response curve, whereas 5MPEP inhibits CPPHA potentiation in a noncompetitive manner. Consistent with this, a mutation (A809V/mGluR5) that reduces binding of ligands to the MPEP site eliminates the effect of VU-29 but has no effect on the response to CPPHA. On the other hand, a mutation (F585I/mGluRs) that eliminates the effect of CPPHA does not alter the response to VU-29. CPPHA is also a PAM at mGluR1. It is interesting that the corresponding mutation of F585I/mGluR5 in mGluR1 (F599I/mGluR1) eliminates CPPHA’s effect without altering the potentiation of a known PAM of mGluR1, (S)-2-(4-fluorophenyl)-1-(toluene-4-sulfonyl)pyrrolidine (Ro 67-7476). Likewise, another mutation (V757L/mGluR1) that abolishes potentiation of Ro 67-7476 has no effect on CPPHA. Finally, CPPHA does not displace binding of a radioligand for the mGluR1 Allosteric antagonist characterized previously. Together, these data suggest that CPPHA acts at a novel Allosteric site on both mGluR1 and -5 to potentiate responses to activation of these receptors.

Atin Lamsal – One of the best experts on this subject based on the ideXlab platform.

  • discovery of a selective m4 positive Allosteric Modulator based on the 3 amino thieno 2 3 b pyridine 2 carboxamide scaffold development of ml253 a potent and brain penetrant compound that is active in a preclinical model of schizophrenia
    Bioorganic & Medicinal Chemistry Letters, 2013
    Co-Authors: Thomas M Bridges, Bruce J Melancon, Atin Lamsal, Paige N Vinson, Thomas J Utley
    Abstract:

    Abstract Herein we report a next generation muscarinic receptor 4 (M4) positive Allosteric Modulator (PAM), ML253 which exhibits nanomolar activity at both the human (EC50 = 56 nM) and rat (EC50 = 176 nM) receptors and excellent efficacy by the left-ward shift of the ACh concentration response curve (fold shift, human = 106; rat = 50). In addition, ML253 is selective against the four other muscarinic subtypes, displays excellent CNS exposure and is active in an amphetamine-induced hyperlocomotion assay.

Yelin Chen – One of the best experts on this subject based on the ideXlab platform.

  • glun2a selective positive Allosteric Modulator nalmefene flumazenil reverses ketamine fentanyl dexmedetomidine induced anesthesia and analgesia in rats
    Scientific Reports, 2020
    Co-Authors: Jia Yan, Dewei Tang, Jidong Zhu, Chen Huang, Yu Sun, Hao Wang, Yelin Chen, Hong Jiang
    Abstract:

    Anesthetics are used to produce hypnosis and analgesic effects during surgery, but anesthesia for a long time after the operation is not conducive to the recovery of animals or patients. Therefore, finding appropriate treatments to counter the effects of anesthetics could enhance postoperative recovery. In the current study, we discovered the novel role of a GluN2A-selective positive Allosteric Modulator (PAM) in ketamine-induced anesthesia and investigated the effects of the PAM combined with nalmefene and flumazenil (PNF) in reversing the actions of an anesthetic combination (ketamine-fentanyl-dexmedetomidine, KFD). PAM treatment dose-dependently decreased the duration of the ketamine-induced loss of righting reflex (LORR). Compared with those in the KFD group, the duration of LORR and the analgesic effect of the KFD + PNF group were obviously decreased. Meanwhile, successive administration of PNF and KFD had no adverse effects on the cardiovascular and respiratory systems. Both the KFD group and the KFD + PNF group showed no changes in hepatic and renal function or cognitive function in rats. Moreover, the recovery of motor coordination of the KFD + PNF group was faster than that of the KFD group. In summary, our results suggest the potential application of the PNF combination as an antagonistic treatment strategy for anesthesia.

  • n 4 chloro 2 1 3 dioxo 1 3 dihydro 2h isoindol 2 yl methyl phenyl 2 hydroxybenzamide cppha acts through a novel site as a positive Allosteric Modulator of group 1 metabotropic glutamate receptors
    Molecular Pharmacology, 2008
    Co-Authors: Yelin Chen, Jeanphilippe Pin, Cyril Goudet, Jeffrey P Conn
    Abstract:

    Recent studies suggest that a novel positive Allosteric Modulator (PAM) of the metabotropic glutamate receptor (mGluRs), mGluR5, termed 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (VU-29), potentiates mGluR5 responses by actions at a site that is overlapping with the binding site of 2-methyl-6-(phenylethynyl)pyridine (MPEP), a previously identified negative Allosteric Modulator of this receptor. It is interesting that a structurally distinct PAM, N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA), does not to bind to the MPEP site. We now report that CPPHA potentiates mGluR5 responses by a mechanism that is distinct from that of VU-29. VU-29- and CPPHA-induced potentiation of mGluR5 responses are blocked by a neutral ligand at the MPEP Allosteric site termed 5-methyl-2-(phenylethynyl)pyridine (5MPEP). However, increasing concentrations of 5MPEP induce parallel rightward shifts in the VU-29 concentration-response curve, whereas 5MPEP inhibits CPPHA potentiation in a noncompetitive manner. Consistent with this, a mutation (A809V/mGluR5) that reduces binding of ligands to the MPEP site eliminates the effect of VU-29 but has no effect on the response to CPPHA. On the other hand, a mutation (F585I/mGluRs) that eliminates the effect of CPPHA does not alter the response to VU-29. CPPHA is also a PAM at mGluR1. It is interesting that the corresponding mutation of F585I/mGluR5 in mGluR1 (F599I/mGluR1) eliminates CPPHA’s effect without altering the potentiation of a known PAM of mGluR1, (S)-2-(4-fluorophenyl)-1-(toluene-4-sulfonyl)pyrrolidine (Ro 67-7476). Likewise, another mutation (V757L/mGluR1) that abolishes potentiation of Ro 67-7476 has no effect on CPPHA. Finally, CPPHA does not displace binding of a radioligand for the mGluR1 Allosteric antagonist characterized previously. Together, these data suggest that CPPHA acts at a novel Allosteric site on both mGluR1 and -5 to potentiate responses to activation of these receptors.

  • N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) acts through a novel site as a positive Allosteric Modulator of group 1 metabotropic glutamate receptors.
    Molecular Pharmacology, 2008
    Co-Authors: Yelin Chen, Cyril Goudet, Jeanphilippe Pin, P. Jeffrey Conn
    Abstract:

    Recent studies suggest that a novel positive Allosteric Modulator (PAM) of the metabotropic glutglutamateeptor (mGluRs), mGluR5, termed 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (VU-29), potentiates mGluR5 responses by actions at a site that is overlapping with the binding site of 2-methyl-6-(phenylethynyl)pyridine (MPEP), a previously identified negative Allosteric Modulator of this receptor. It is interesting that a structurally distinct PAM, N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA), does not to bind to the MPEP site. We now report that CPPHA potentiates mGluR5 responses by a mechanism that is distinct from that of VU-29. VU-29- and CPPHA-induced potentiation of mGluR5 responses are blocked by a neutral ligand at the MPEP Allosteric site termed 5-methyl-2-(phenylethynyl)pyridine (5MPEP). However, increasing concentrations of 5MPEP induce parallel rightward shifts in the VU-29 concentration-response curve, whereas 5MPEP inhibits CPPHA potentiation in a noncompetitive manner. Consistent with this, a mutation (A809V/mGluR5) that reduces binding of ligands to the MPEP site eliminates the effect of VU-29 but has no effect on the response to CPPHA. On the other hand, a mutation (F585I/mGluRs) that eliminates the effect of CPPHA does not alter the response to VU-29. CPPHA is also a PAM at mGluR1. It is interesting that the corresponding mutation of F585I/mGluR5 in mGluR1 (F599I/mGluR1) eliminates CPPHA’s effect without altering the potentiation of a known PAM of mGluR1, (S)-2-(4-fluorophenyl)-1-(toluene-4-sulfonyl)pyrrolidine (Ro 67-7476). Likewise, another mutation (V757L/mGluR1) that abolishes potentiation of Ro 67-7476 has no effect on CPPHA. Finally, CPPHA does not displace binding of a radioligand for the mGluR1 Allosteric antagonist characterized previously. Together, these data suggest that CPPHA acts at a novel Allosteric site on both mGluR1 and -5 to potentiate responses to activation of these receptors.