Positive allosteric modulatory effects of ajulemic acid at strychnine-sensitive glycine alpha1- and alpha1beta-receptors.

Abstract

The synthetic cannabinoid ajulemic acid (CT-3) is a potent cannabinoid receptor agonist which was found to reduce pain scores in neuropathic pain patients in the absence of cannabis-like psychotropic adverse effects. The reduced psychotropic activity of ajulemic acid has been attributed to a greater contribution of peripheral CB receptors to its mechanism of action as well as to non-CB receptor mechanisms. Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. As we hypothesised that additional non-CB receptor mechanisms of ajulemic acid might contribute to its effect in neuropathic pain, we investigated the interaction of ajulemic acid with strychnine-sensitive alpha(1)- and alpha(1)beta-glycine receptors by using the whole-cell patch clamp technique. Ajulemic acid showed a positive allosteric modulating effect in a concentration range which can be considered close to clinically relevant concentrations (EC(50) values: alpha(1) = 9.7 +/- 2.6 microM and alpha(1)beta = 12.4 +/- 3.4 microM). Direct activation of glycine receptors was observed at higher concentrations above 100 microM (EC(50) values: alpha(1) = 140.9 +/- 21.5 microM and alpha(1)beta = 154.3 +/- 32.1 microM). These in vitro results demonstrate that ajulemic acid modulates strychnine-sensitive glycine receptors in clinically relevant concentrations.

• Authors: Jörg Ahrens, Martin Leuwer, Reyhan Demir, Klaus Krampfl, Jeanne de la Roche, Nilufar Foadi, Matthias Karst, Gertrud Haeseler
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 379 Issue 4 Pg. 371-8 (Apr 2009) ISSN: 1432-1912 [Electronic] Germany
• PMID: 18985319 (Publication Type: Journal Article)

Chemical References

• GLRB protein, human
• Receptors, Glycine
• Receptors, Neurotransmitter
• strychnine receptor
• Dronabinol
• lenabasum
• Glycine

Topics

• Cell Line
• Dronabinol (analogs & derivatives, pharmacology)
• Electrophysiological Phenomena (drug effects)
• Glycine (pharmacology)
• Humans
• Patch-Clamp Techniques
• Protein Conformation (drug effects)
• Receptors, Glycine (agonists, drug effects, genetics)
• Receptors, Neurotransmitter (agonists, drug effects, genetics)
• Transfection