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Molecular-interaction and signaling profiles of AM3677, a novel covalent agonist selective for the cannabinoid 1 receptor

Academic Article
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Overview

authors

  • Janero, D. R.
  • Yaddanapudi, S.
  • Zvonok, N.
  • Subramanian, K. V.
  • Shukla, V. G.
  • Stahl, E.
  • Zhou, L.
  • Hurst, D.
  • Wager-Miler, J.
  • Bohn, Laura
  • Reggio, P. H.
  • Mackie, K.
  • Makriyannis, A.

publication date

  • 2015

journal

  • ACS Chemical Neuroscience  Journal

abstract

  • The cannabinoid 1 receptor (CB1R) is one of the most abundant G protein-coupled receptors (GPCRs) in the central nervous system. CB1R involvement in multiple physiological processes, especially neurotransmitter release and synaptic function, has made this GPCR a prime drug discovery target, and pharmacological CB1R activation has been demonstrated to be a tenable therapeutic modality. Accordingly, the design and profiling of novel, drug-like CB1R modulators to inform the receptor's ligand-interaction landscape and molecular pharmacology constitute a prime contemporary research focus. For this purpose, we report utilization of AM3677, a designer endocannabinoid (anandamide) analogue derivatized with a reactive electrophilic isothiocyanate functionality, as a covalent, CB1R-selective chemical probe. The data demonstrate that reaction of AM3677 with a cysteine residue in transmembrane helix 6 of human CB1R (hCB1R), C6.47(355), is a key feature of AM3677's ligand-binding motif. Pharmacologically, AM3677 acts as a high-affinity, low-efficacy CB1R agonist that inhibits forskolin-stimulated cellular cAMP formation and stimulates CB1R coupling to G protein. AM3677 also induces CB1R endocytosis and irreversible receptor internalization. Computational docking suggests the importance of discrete hydrogen bonding and aromatic interactions as determinants of AM3677's topology within the ligand-binding pocket of active-state hCB1R. These results constitute the initial identification and characterization of a potent, high-affinity, hCB1R-selective covalent agonist with utility as a pharmacologically active, orthosteric-site probe for providing insight into structure-function correlates of ligand-induced CB1R activation and the molecular features of that activation by the native ligand, anandamide.

subject areas

  • Animals
  • Arachidonic Acids
  • Cannabinoid Receptor Agonists
  • Cell Membrane
  • Colforsin
  • Cyclic AMP
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Endocytosis
  • HEK293 Cells
  • Hippocampus
  • Humans
  • Hydrogen Bonding
  • Isothiocyanates
  • Mice
  • Molecular Docking Simulation
  • Molecular Structure
  • Mutation
  • Radioligand Assay
  • Receptor, Cannabinoid, CB1
  • Transfection
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Research

keywords

  • 7-transmembrane receptor
  • Amino acid
  • G protein-coupled receptor
  • binding domain
  • central nervous system
  • chemical probe
  • cysteine
  • homology modeling
  • isothiocyanate
  • ligand-binding motif
  • receptor activation
  • signal transduction
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Identity

PubMed Central ID

  • PMC4804703

International Standard Serial Number (ISSN)

  • 1948-7193

Digital Object Identifier (DOI)

  • 10.1021/acschemneuro.5b00090

PubMed ID

  • 25978068
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Additional Document Info

start page

  • 1400

end page

  • 1410

volume

  • 6

issue

  • 8

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