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Molecular Pharmacology

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Research ArticleArticle

Effects of the Allosteric Antagonist 1-(4-Chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl]urea (PSNCBAM-1) on CB1 Receptor Modulation in the Cerebellum

Xiaowei Wang, James G. Horswill, Benjamin J. Whalley and Gary J. Stephens
Molecular Pharmacology April 2011, 79 (4) 758-767; DOI: https://doi.org/10.1124/mol.110.068197
Xiaowei Wang
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James G. Horswill
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Benjamin J. Whalley
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Gary J. Stephens
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Abstract

1-(4-Chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl] urea (PSNCBAM-1) has recently been described as a cannabinoid CB1 receptor allosteric antagonist associated with hypophagic effects in vivo; however, PSNCBAM-1 effects on CB1 ligand-mediated modulation of neuronal excitability remain unknown. Here, we investigate PSNCBAM-1 actions on CB1 receptor-stimulated guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding in cerebellar membranes and on CB1 ligand modulation of presynaptic CB1 receptors at inhibitory interneuron-Purkinje cell synapses in the cerebellum using whole-cell electrophysiology. PSNCBAM-1 caused noncompetitive antagonism in [35S]GTPγS binding studies, with higher potency against the CB receptor agonist (−)-cis-3-[2-hydroxy-4-(1,1-dimethyl heptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940) than for R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]-pyrrolo[1,2,3,-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate] [WIN55,212-2 (WIN55)]. In electrophysiological studies, WIN55 and CP55940 reduced miniature inhibitory postsynaptic currents (mIPSCs) frequency but not amplitude. PSNCBAM-1 application alone had no effect on mIPSCs; however, PSNCBAM-1 pretreatment revealed agonist-dependent functional antagonism, abolishing CP55940-induced reductions in mIPSC frequency but having no clear effect on WIN55 actions. The CB1 antagonist/inverse agonist N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-multipyrazole-3-carboxamide (AM251) increased mIPSC frequency beyond control; this effect was reversed by PSNCBAM-1. PSNCBAM-1 pretreatment also attenuated AM251 effects. Thus, PSNCBAM-1 reduced CB1 receptor ligand functional efficacy in the cerebellum. The differential effect of PSNCBAM-1 on CP55940 versus WIN55 actions in [35S]GTPγS binding and electrophysiological studies and the attenuation of AM251 effects are consistent with the ligand-dependence associated with allosteric modulation. These data provide the first description of functional PSNCBAM-1 allosteric antagonist effects on neuronal excitability in the mammalian central nervous system (CNS). PSNCBAM-1 allosteric antagonism may provide viable therapeutic alternatives to orthosteric CB1 antagonists/inverse agonists in the treatment of CNS disease.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • This work was funded by an Ataxia UK Studentship and by a University of Reading International Postgraduate Research Studentship.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/mol.110.068197.

  • ABBREVIATIONS:

    GPCR
    G protein-coupled receptor
    AM251
    N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-multipyrazole-3-carboxamide
    CP55940
    (−)-cis-3-[2-hydroxy-4-(1,1-dimethyl heptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol; PSNCBAM-1,1-(4-chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl]urea
    WIN55,212-2 (WIN55)
    R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]-pyrrolo[1,2,3,-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate
    IN
    interneuron
    PC
    Purkinje cell
    mIPSC
    miniature inhibitory postsynaptic current
    CB
    cannabinoid
    aCSF
    artificial cerebrospinal fluid
    TTX
    tetrodotoxin
    ANOVA
    analysis of variance
    HSD
    honestly significant difference
    Δ9-THCV
    Δ9-tetrahydrocannabivarin
    NBQX
    2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline
    SR141716A
    N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride
    [35S]GTPγS
    guanosine 5′-O-(3-[35S]thio)triphosphate
    O-1602
    5-methyl-4-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-1,3-benzenediol.

  • Received August 21, 2010.
  • Accepted December 15, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (4)
Molecular Pharmacology
Vol. 79, Issue 4
1 Apr 2011
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Research ArticleArticle

Effects of the Allosteric Antagonist 1-(4-Chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl]urea (PSNCBAM-1) on CB1 Receptor Modulation in the Cerebellum

Xiaowei Wang, James G. Horswill, Benjamin J. Whalley and Gary J. Stephens
Molecular Pharmacology April 1, 2011, 79 (4) 758-767; DOI: https://doi.org/10.1124/mol.110.068197

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Research ArticleArticle

Effects of the Allosteric Antagonist 1-(4-Chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl]urea (PSNCBAM-1) on CB1 Receptor Modulation in the Cerebellum

Xiaowei Wang, James G. Horswill, Benjamin J. Whalley and Gary J. Stephens
Molecular Pharmacology April 1, 2011, 79 (4) 758-767; DOI: https://doi.org/10.1124/mol.110.068197
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