The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Alan P Kozikowski - One of the best experts on this subject based on the ideXlab platform.

  • discovery of n substituted 2 phenylcyclopropyl methylamines as functionally selective serotonin 2c receptor agonists for potential use as Antipsychotic medications
    Journal of Medicinal Chemistry, 2017
    Co-Authors: Guiping Zhang, John D Mccorvy, Paul J Lorello, Barbara J Caldarone, Bryan L Roth, Jianjun Cheng, Alan P Kozikowski
    Abstract:

    A series of N-substituted (2-phenylcyclopropyl)methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT2C)-selective agonists with a preference for Gq signaling. A number of these compounds exhibit 5-HT2C selectivity with a preference for Gq-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC50 of 23 nM in the calcium flux assay while showing no β-arrestin recruitment Activity, is the most functionally selective 5-HT2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC50 of 24 nM at the 5-HT2C receptor, is fully selective over the 5-HT2B receptor. In an amphetamine-induced hyperActivity model, compound (+)-19 showed significant Antipsychotic-drug-like Activity. These novel compounds shed light on the role of functional selectivity at the 5-HT2C receptor with respect to Antipsychotic Activity.

  • Discovery of N‑Substituted (2-Phenylcyclopropyl)methylamines as Functionally Selective Serotonin 2C Receptor Agonists for Potential Use as Antipsychotic Medications
    2017
    Co-Authors: Guiping Zhang, John D Mccorvy, Paul J Lorello, Barbara J Caldarone, Bryan L Roth, Jianjun Cheng, Alan P Kozikowski
    Abstract:

    A series of N-substituted (2-phenylcyclopropyl)­methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT2C)-selective agonists with a preference for Gq signaling. A number of these compounds exhibit 5-HT2C selectivity with a preference for Gq-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC50 of 23 nM in the calcium flux assay while showing no β-arrestin recruitment Activity, is the most functionally selective 5-HT2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC50 of 24 nM at the 5-HT2C receptor, is fully selective over the 5-HT2B receptor. In an amphetamine-induced hyperActivity model, compound (+)-19 showed significant Antipsychotic-drug-like Activity. These novel compounds shed light on the role of functional selectivity at the 5-HT2C receptor with respect to Antipsychotic Activity

Guiping Zhang - One of the best experts on this subject based on the ideXlab platform.

  • discovery of n substituted 2 phenylcyclopropyl methylamines as functionally selective serotonin 2c receptor agonists for potential use as Antipsychotic medications
    Journal of Medicinal Chemistry, 2017
    Co-Authors: Guiping Zhang, John D Mccorvy, Paul J Lorello, Barbara J Caldarone, Bryan L Roth, Jianjun Cheng, Alan P Kozikowski
    Abstract:

    A series of N-substituted (2-phenylcyclopropyl)methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT2C)-selective agonists with a preference for Gq signaling. A number of these compounds exhibit 5-HT2C selectivity with a preference for Gq-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC50 of 23 nM in the calcium flux assay while showing no β-arrestin recruitment Activity, is the most functionally selective 5-HT2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC50 of 24 nM at the 5-HT2C receptor, is fully selective over the 5-HT2B receptor. In an amphetamine-induced hyperActivity model, compound (+)-19 showed significant Antipsychotic-drug-like Activity. These novel compounds shed light on the role of functional selectivity at the 5-HT2C receptor with respect to Antipsychotic Activity.

  • Discovery of N‑Substituted (2-Phenylcyclopropyl)methylamines as Functionally Selective Serotonin 2C Receptor Agonists for Potential Use as Antipsychotic Medications
    2017
    Co-Authors: Guiping Zhang, John D Mccorvy, Paul J Lorello, Barbara J Caldarone, Bryan L Roth, Jianjun Cheng, Alan P Kozikowski
    Abstract:

    A series of N-substituted (2-phenylcyclopropyl)­methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT2C)-selective agonists with a preference for Gq signaling. A number of these compounds exhibit 5-HT2C selectivity with a preference for Gq-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC50 of 23 nM in the calcium flux assay while showing no β-arrestin recruitment Activity, is the most functionally selective 5-HT2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC50 of 24 nM at the 5-HT2C receptor, is fully selective over the 5-HT2B receptor. In an amphetamine-induced hyperActivity model, compound (+)-19 showed significant Antipsychotic-drug-like Activity. These novel compounds shed light on the role of functional selectivity at the 5-HT2C receptor with respect to Antipsychotic Activity

Alice L Rodriguez - One of the best experts on this subject based on the ideXlab platform.

  • functional impact of allosteric agonist Activity of selective positive allosteric modulators of metabotropic glutamate receptor subtype 5 in regulating central nervous system function
    Molecular Pharmacology, 2012
    Co-Authors: Meredith J Noetzel, Alice L Rodriguez, Ya Zhou, Emily Days, Jerri M Rook, Paige N Vinson, Hilde Lavreysen, Shaun R Stauffer, Colleen M Niswender, Zixiu Xiang
    Abstract:

    Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) have emerged as an exciting new approach for the treatment of schizophrenia and other central nervous system (CNS) disorders. Of interest, some mGlu5 PAMs act as pure PAMs, only potentiating mGlu5 responses to glutamate whereas others [allosteric agonists coupled with PAM Activity (ago-PAMs)] potentiate responses to glutamate and have intrinsic allosteric agonist Activity in mGlu5-expressing cell lines. All mGlu5 PAMs previously shown to have efficacy in animal models act as ago-PAMs in cell lines, raising the possibility that allosteric agonist Activity is critical for in vivo efficacy. We have now optimized novel mGlu5 pure PAMs that are devoid of detectable agonist Activity and structurally related mGlu5 ago-PAMs that activate mGlu5 alone in cell lines. Studies of mGlu5 PAMs in cell lines revealed that ago-PAM Activity is dependent on levels of mGlu5 receptor expression in human embryonic kidney 293 cells, whereas PAM potency is relatively unaffected by levels of receptor expression. Furthermore, ago-PAMs have no agonist Activity in the native systems tested, including cortical astrocytes and subthalamic nucleus neurons and in measures of long-term depression at the hippocampal Schaffer collateral-CA1 synapse. Finally, studies with pure PAMs and ago-PAMs chemically optimized to provide comparable CNS exposure revealed that both classes of mGlu5 PAMs have similar efficacy in a rodent model predictive of Antipsychotic Activity. These data suggest that the level of receptor expression influences the ability of mGlu5 PAMs to act as allosteric agonists in vitro and that ago-PAM Activity observed in cell-based assays may not be important for in vivo efficacy.

  • discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo Activity in rat behavioral models of anxiolytic and Antipsychotic Activity
    Molecular Pharmacology, 2010
    Co-Authors: Alice L Rodriguez, Mark D Grier, Carrie K Jones, Elizabeth J Herman, Alexander S Kane, Randy L Smith, Richard Williams, Ya Zhou, Joy E Marlo, Emily Days
    Abstract:

    Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders, including anxiety and schizophrenia. Although compounds have been developed to better understand the physiological roles of mGluR5 and potential usefulness for the treatment of these disorders, there are limitations in the tools available, including poor selectivity, low potency, and limited solubility. To address these issues, we developed an innovative assay that allows simultaneous screening for mGluR5 agonists, antagonists, and potentiators. We identified multiple scaffolds that possess diverse modes of Activity at mGluR5, including both positive and negative allosteric modulators (PAMs and NAMs, respectively). 3-Fluoro-5-(3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (VU0285683) was developed as a novel selective mGluR5 NAM with high affinity for the 2-methyl-6-(phenylethynyl)-pyridine (MPEP) binding site. VU0285683 had anxiolytic-like Activity in two rodent models for anxiety but did not potentiate phencyclidine-induced hyperlocomotor Activity. (4-Hydroxypiperidin-1-yl)(4-phenylethynyl)phenyl)methanone (VU0092273) was identified as a novel mGluR5 PAM that also binds to the MPEP site. VU0092273 was chemically optimized to an orally active analog, N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide hydrochloride (VU0360172), which is selective for mGluR5. This novel mGluR5 PAM produced a dose-dependent reversal of amphetamine-induced hyperlocomotion, a rodent model predictive of Antipsychotic Activity. Discovery of structurally and functionally diverse allosteric modulators of mGluR5 that demonstrate in vivo efficacy in rodent models of anxiety and Antipsychotic Activity provide further support for the tremendous diversity of chemical scaffolds and modes of efficacy of mGluR5 ligands. In addition, these studies provide strong support for the hypothesis that multiple structurally distinct mGluR5 modulators have robust Activity in animal models that predict efficacy in the treatment of CNS disorders.

  • discovery of molecular switches that modulate modes of metabotropic glutamate receptor subtype 5 mglu5 pharmacology in vitro and in vivo within a series of functionalized regioisomeric 2 and 5 phenylethynyl pyrimidines
    Journal of Medicinal Chemistry, 2009
    Co-Authors: Sameer Sharma, Alice L Rodriguez, Carrie K Jones, Randy L Smith, Jeffrey P Conn, Jeffrey Kedrowski, Jerri M Rook, Craig W Lindsley
    Abstract:

    We describe the synthesis and SAR of a series of analogues of the mGlu5 partial antagonist 5-(phenylethynyl)pyrimidine. New molecular switches are identified that modulate the pharmacological Activity of the lead compound. Slight structural modifications around the proximal pyrimidine ring change Activity of the partial antagonist lead to that of potent and selective full negative allosteric modulators and positive allosteric modulators, which demonstrate in vivo efficacy in rodent models for anxiolytic and Antipsychotic Activity, respectively.

  • a selective allosteric potentiator of metabotropic glutamate mglu 2 receptors has effects similar to an orthosteric mglu2 3 receptor agonist in mouse models predictive of Antipsychotic Activity
    Journal of Pharmacology and Experimental Therapeutics, 2005
    Co-Authors: Ruggero Galici, Alice L Rodriguez, Nicholas G Echemendia, Jeffrey P Conn
    Abstract:

    Recent studies suggest that agonists of group II metabotropic glutamate (mGlu) receptors (mGlu2/3) have potential utility as novel therapeutic agents for treatment of psychiatric disorders such as anxiety and schizophrenia. Agonists of mGlu2/3 receptors block amphetamine- and phencyclidine (PCP)-induced hyperlocomotor Activity in rodents, two actions that may predict potential Antipsychotic Activity of these compounds. We now report that LY487379 [N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine], a recently described selective allosteric potentiator of mGlu2 receptor, has behavioral effects similar to mGlu2/3 receptor agonists. LY487379 and LY379268 [(-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate], an ortho-steric mGlu2/3 receptor agonist, induced similar dose-dependent reductions in PCP- and amphetamine-induced hyperlocomotor Activity in C57BL6/J mice at doses that did not significantly alter spontaneous locomotor Activity. These effects were blocked by the mGlu2/3 receptor antagonist LY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid]. LY487379 had a short duration of action compared with LY379268. Furthermore, unlike the mGlu2/3 agonist, LY487379 reversed amphetamine-induced disruption of prepulse inhibition of the acoustic startle reflex. When LY379268 was given chronically, it failed to block amphetamine- and PCP-induced hyperlocomotor Activity. The finding that the effects of an orthosteric mGlu2/3 receptor agonist in these models can be mimicked by a selective allosteric potentiator of mGlu2 suggests that these effects are mediated by the mGlu2 receptor subtype. Furthermore, these data raise the possibility that a selective allosteric potentiator of mGlu2 receptor could have utility as a novel approach for the treatment of schizophrenia.

Barbara J Caldarone - One of the best experts on this subject based on the ideXlab platform.

  • discovery of n substituted 2 phenylcyclopropyl methylamines as functionally selective serotonin 2c receptor agonists for potential use as Antipsychotic medications
    Journal of Medicinal Chemistry, 2017
    Co-Authors: Guiping Zhang, John D Mccorvy, Paul J Lorello, Barbara J Caldarone, Bryan L Roth, Jianjun Cheng, Alan P Kozikowski
    Abstract:

    A series of N-substituted (2-phenylcyclopropyl)methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT2C)-selective agonists with a preference for Gq signaling. A number of these compounds exhibit 5-HT2C selectivity with a preference for Gq-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC50 of 23 nM in the calcium flux assay while showing no β-arrestin recruitment Activity, is the most functionally selective 5-HT2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC50 of 24 nM at the 5-HT2C receptor, is fully selective over the 5-HT2B receptor. In an amphetamine-induced hyperActivity model, compound (+)-19 showed significant Antipsychotic-drug-like Activity. These novel compounds shed light on the role of functional selectivity at the 5-HT2C receptor with respect to Antipsychotic Activity.

  • Discovery of N‑Substituted (2-Phenylcyclopropyl)methylamines as Functionally Selective Serotonin 2C Receptor Agonists for Potential Use as Antipsychotic Medications
    2017
    Co-Authors: Guiping Zhang, John D Mccorvy, Paul J Lorello, Barbara J Caldarone, Bryan L Roth, Jianjun Cheng, Alan P Kozikowski
    Abstract:

    A series of N-substituted (2-phenylcyclopropyl)­methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT2C)-selective agonists with a preference for Gq signaling. A number of these compounds exhibit 5-HT2C selectivity with a preference for Gq-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC50 of 23 nM in the calcium flux assay while showing no β-arrestin recruitment Activity, is the most functionally selective 5-HT2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC50 of 24 nM at the 5-HT2C receptor, is fully selective over the 5-HT2B receptor. In an amphetamine-induced hyperActivity model, compound (+)-19 showed significant Antipsychotic-drug-like Activity. These novel compounds shed light on the role of functional selectivity at the 5-HT2C receptor with respect to Antipsychotic Activity

Paul J Lorello - One of the best experts on this subject based on the ideXlab platform.

  • discovery of n substituted 2 phenylcyclopropyl methylamines as functionally selective serotonin 2c receptor agonists for potential use as Antipsychotic medications
    Journal of Medicinal Chemistry, 2017
    Co-Authors: Guiping Zhang, John D Mccorvy, Paul J Lorello, Barbara J Caldarone, Bryan L Roth, Jianjun Cheng, Alan P Kozikowski
    Abstract:

    A series of N-substituted (2-phenylcyclopropyl)methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT2C)-selective agonists with a preference for Gq signaling. A number of these compounds exhibit 5-HT2C selectivity with a preference for Gq-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC50 of 23 nM in the calcium flux assay while showing no β-arrestin recruitment Activity, is the most functionally selective 5-HT2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC50 of 24 nM at the 5-HT2C receptor, is fully selective over the 5-HT2B receptor. In an amphetamine-induced hyperActivity model, compound (+)-19 showed significant Antipsychotic-drug-like Activity. These novel compounds shed light on the role of functional selectivity at the 5-HT2C receptor with respect to Antipsychotic Activity.

  • Discovery of N‑Substituted (2-Phenylcyclopropyl)methylamines as Functionally Selective Serotonin 2C Receptor Agonists for Potential Use as Antipsychotic Medications
    2017
    Co-Authors: Guiping Zhang, John D Mccorvy, Paul J Lorello, Barbara J Caldarone, Bryan L Roth, Jianjun Cheng, Alan P Kozikowski
    Abstract:

    A series of N-substituted (2-phenylcyclopropyl)­methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT2C)-selective agonists with a preference for Gq signaling. A number of these compounds exhibit 5-HT2C selectivity with a preference for Gq-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC50 of 23 nM in the calcium flux assay while showing no β-arrestin recruitment Activity, is the most functionally selective 5-HT2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC50 of 24 nM at the 5-HT2C receptor, is fully selective over the 5-HT2B receptor. In an amphetamine-induced hyperActivity model, compound (+)-19 showed significant Antipsychotic-drug-like Activity. These novel compounds shed light on the role of functional selectivity at the 5-HT2C receptor with respect to Antipsychotic Activity