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Enantiomer-specific positive allosteric modulation of CB1 signaling in autaptic hippocampal neurons
- Publication Year :
- 2017
-
Abstract
- The cannabinoid signaling system is found throughout the CNS and its involvement in several pathological processes makes it an attractive therapeutic target. Because orthosteric CB1 cannabinoid receptor ligands have undesirable adverse effects there has been great interest in the development of allosteric modulators - both negative (NAMs) and positive (PAMs) - of these receptors. NAMs of CB1 appeared first on the scene, followed more recently by PAMs. Because allosteric modulation can vary depending on the orthosteric ligand it is important to study their function in a system that employs endogenous cannabinoids. We have recently surveyed first generation NAMs using cultured autaptic hippocampal neurons. These neurons express depolarization induced suppression of excitation (DSE), a form of synaptic plasticity that is mediated by CB1 and 2-arachidonoyl glycerol (2-AG); they are therefore an excellent neuronal model of endogenous cannabinoid signaling in which to test CB1 modulators. In this study we find that while two related compounds, GAT211 and ZCZ011, each show PAM-like responses in autaptic hippocampal neurons, they also exhibit complex pharmacology. Notably we were able to separate the PAM- and agonist-like responses of GAT211 by examining the enantiomers of this racemic compound: GAT228 and GAT229. We find that GAT229 exhibits PAM-like behavior while GAT228 appears to directly activate the CB1 receptor. Both GAT229 and ZCZ011 represent the first PAMs that we have found to be effective in using this 2-AG utilizing neuronal model system. Because these compounds may exhibit both probe selectivity and biased signaling it will be important to test them with anandamide as well as other signaling pathways.
- Subjects :
- 0301 basic medicine
Cannabinoid receptor
Indoles
medicine.medical_treatment
Allosteric regulation
Thiophenes
Hippocampal formation
Hippocampus
Article
03 medical and health sciences
0302 clinical medicine
Allosteric Regulation
Receptor, Cannabinoid, CB1
medicine
Animals
G protein-coupled receptor
Pharmacology
Cannabinoid Receptor Agonists
Mice, Knockout
Neurons
Chemistry
food and beverages
Depolarization
Stereoisomerism
Mice, Inbred C57BL
030104 developmental biology
nervous system
Synaptic plasticity
lipids (amino acids, peptides, and proteins)
Cannabinoid
Signal transduction
Neuroscience
030217 neurology & neurosurgery
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....66be66c72eca4c0bdbd6776b5fd87107