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In vivo evaluation of the CB 1 allosteric modulator LDK1258 reveals CB 1 -receptor independent behavioral effects.
- Source :
-
Pharmacology, biochemistry, and behavior [Pharmacol Biochem Behav] 2020 Mar; Vol. 190, pp. 172840. Date of Electronic Publication: 2019 Dec 30. - Publication Year :
- 2020
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Abstract
- In the present study, we examined whether LDK1258, which produces strong CB <subscript>1</subscript> 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 CB <subscript>1</subscript> (-/-) 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 CB <subscript>1</subscript> receptor mediated. Additionally, LDK1258 did not substitute for the CB <subscript>1</subscript> receptor orthosteric agonists CP55,940 or anandamide in the drug discrimination paradigm. In other in vivo assays sensitive to CB <subscript>1</subscript> 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 CB <subscript>1</subscript> receptor allosterism. More generally, this study offers a straightforward screening assay to determine whether newly synthesized CB <subscript>1</subscript> receptor allosteric modulators translate to the whole animal.<br /> (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Subjects :
- Allosteric Regulation
Amidohydrolases genetics
Animals
Arachidonic Acids pharmacology
Cannabinoid Receptor Agonists pharmacology
Cannabinoid Receptor Antagonists pharmacology
Chromatography, Liquid
Cyclohexanols pharmacology
Disease Models, Animal
Endocannabinoids pharmacology
Female
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Polyunsaturated Alkamides pharmacology
Receptor, Cannabinoid, CB1 genetics
Rimonabant pharmacology
Tandem Mass Spectrometry
Analgesics pharmacology
Appetite Depressants pharmacology
Behavior, Animal drug effects
Locomotion drug effects
Neuralgia drug therapy
Receptor, Cannabinoid, CB1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1873-5177
- Volume :
- 190
- Database :
- MEDLINE
- Journal :
- Pharmacology, biochemistry, and behavior
- Publication Type :
- Academic Journal
- Accession number :
- 31899221
- Full Text :
- https://doi.org/10.1016/j.pbb.2019.172840