In vivo evaluation of the CB1 allosteric modulator LDK1258 reveals CB1-receptor independent behavioral effects.

Abstract

In the present study, we examined whether LDK1258, which produces strong CB1 receptor allosteric effects in in vitro assays, would elicit in vivo effects consistent with allosteric activity. In initial studies, LDK1258 reduced food consumption and elicited delayed antinociceptive effects in the chronic constrictive injury of the sciatic nerve (CCI) model of neuropathic pain, which unexpectedly emerged 4 h post-injection. UPLC-MS/MS analysis quantified significant levels of LDK1258 in both blood and brain tissue at 30 min post-administration that remained stable up to 4 h. The observation that LDK1258 also produced respective antinociceptive and anorectic effects in rimonabant-treated wild type mice and CB1 (-/-) mice suggests an off-target mechanism of action. Likewise, LDK1258 produced a partial array of common cannabimimetic effects in the tetrad assay, which were not CB1 receptor mediated. Additionally, LDK1258 did not substitute for the CB1 receptor orthosteric agonists CP55,940 or anandamide in the drug discrimination paradigm. In other in vivo assays sensitive to CB1 receptor allosteric modulators, LDK1258 failed to shift the dose-response curves of either CP55,940 or anandamide in producing thermal antinociception, catalepsy, or hypothermia, and did not alter the generalization curve of either drug in the drug discrimination assay. Thus, this battery of tests yielded results demonstrating that LDK1258 produces antinociceptive effects in the CCI model of neuropathic pain, anorectic effects, and other in vivo pharmacological effects in a manner inconsistent with CB1 receptor allosterism. More generally, this study offers a straightforward screening assay to determine whether newly synthesized CB1 receptor allosteric modulators translate to the whole animal.

• Authors: Mohammed Mustafa, Giulia Donvito, Lauren Moncayo, Amelia Swafford, Justin Poklis, Ralph Grauer, Teresa Olszewska, Bogna Ignatowska-Jankowska, Debra A Kendall, Dai Lu, Aron H Lichtman
• Journal: Pharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 190 Pg. 172840 (03 2020) ISSN: 1873-5177 [Electronic] United States
• PMID: 31899221 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Analgesics
• Appetite Depressants
• Arachidonic Acids
• CNR1 protein, mouse
• Cannabinoid Receptor Agonists
• Cannabinoid Receptor Antagonists
• Cyclohexanols
• Endocannabinoids
• Polyunsaturated Alkamides
• Receptor, Cannabinoid, CB1
• 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
• Amidohydrolases
• fatty-acid amide hydrolase
• Rimonabant
• anandamide

Topics

• Allosteric Regulation
• Amidohydrolases (genetics)
• Analgesics (pharmacology)
• Animals
• Appetite Depressants (pharmacology)
• Arachidonic Acids (pharmacology)
• Behavior, Animal (drug effects)
• Cannabinoid Receptor Agonists (pharmacology)
• Cannabinoid Receptor Antagonists (pharmacology)
• Chromatography, Liquid
• Cyclohexanols (pharmacology)
• Disease Models, Animal
• Endocannabinoids (pharmacology)
• Female
• Locomotion (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neuralgia (drug therapy)
• Polyunsaturated Alkamides (pharmacology)
• Receptor, Cannabinoid, CB1 (genetics, metabolism)
• Rimonabant (pharmacology)
• Tandem Mass Spectrometry