Back to Search
Start Over
Molecular-interaction and signaling profiles of AM3677, a novel covalent agonist selective for the cannabinoid 1 receptor.
- Source :
-
ACS chemical neuroscience [ACS Chem Neurosci] 2015 Aug 19; Vol. 6 (8), pp. 1400-10. Date of Electronic Publication: 2015 May 29. - Publication Year :
- 2015
-
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.
- Subjects :
- Animals
Arachidonic Acids chemistry
Cannabinoid Receptor Agonists chemistry
Cell Membrane drug effects
Cell Membrane metabolism
Colforsin
Cyclic AMP metabolism
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Endocytosis drug effects
HEK293 Cells
Hippocampus drug effects
Hippocampus metabolism
Humans
Hydrogen Bonding
Isothiocyanates chemistry
Mice
Molecular Docking Simulation
Molecular Structure
Mutation
Radioligand Assay
Receptor, Cannabinoid, CB1 genetics
Receptor, Cannabinoid, CB1 metabolism
Transfection
Arachidonic Acids pharmacology
Cannabinoid Receptor Agonists pharmacology
Isothiocyanates pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1948-7193
- Volume :
- 6
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- ACS chemical neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 25978068
- Full Text :
- https://doi.org/10.1021/acschemneuro.5b00090