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Pharmacol Res. 2018 Mar;129:475-481. doi: 10.1016/j.phrs.2017.11.019. Epub 2017 Nov 20.

Enantiomer-specific positive allosteric modulation of CB1 signaling in autaptic hippocampal neurons.

Author information

1
Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, 47405-7007, USA.
2
Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, MA, 02115, USA.
3
Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
4
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S1A8, Canada.
5
Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, 47405-7007, USA. Electronic address: straiker@indiana.edu.

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.

KEYWORDS:

Allosteric; CB1; Cannabinoid receptor; G protein-coupled receptor; Orthosteric

PMID:
29158048
PMCID:
PMC5828971
DOI:
10.1016/j.phrs.2017.11.019
[Indexed for MEDLINE]
Free PMC Article

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