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In vivoevaluation of the CB1allosteric modulator LDK1258 reveals CB1-receptor independent behavioral effects
Abstract
In the present study, we examined whether LDK1258, which produces strong CB1receptor allosteric effects ininvitroassays, would elicitin vivoeffects consistent with allosteric activity. In initial studies, LDK1258 reducedfood consumption and elicited delayed antinociceptive effects in the chronic constrictive injury of the sciaticnerve (CCI) model of neuropathic pain, which unexpectedly emerged 4 h post-injection. UPLC-MS/MS analysisquantified significant levels of LDK1258 in both blood and brain tissue at 30 min post-administration thatremained stable up to 4 h. The observation that LDK1258 also produced respective antinociceptive and anorecticeffects 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 werenot CB1receptor mediated. Additionally, LDK1258 did not substitute for the CB1receptor orthosteric agonistsCP55,940 or anandamide in the drug discrimination paradigm. In otherinvivoassays sensitive to CB1receptorallosteric modulators, LDK1258 failed to shift the dose-response curves of either CP55,940 or anandamide inproducing thermal antinociception, catalepsy, or hypothermia, and did not alter the generalization curve ofeither drug in the drug discrimination assay. Thus, this battery of tests yielded results demonstrating thatLDK1258 produces antinociceptive effects in the CCI model of neuropathic pain, anorectic effects, and otherinvivopharmacological effects in a manner inconsistent with CB1receptor allosterism. More generally, this studyoffers a straightforward screening assay to determine whether newly synthesized CB1receptor allosteric mod-ulators translate to the whole animal.
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Authors (11)
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Mustafa Mohammed
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Giulia Donvito
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Lauren Moncayo
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Amelia Swafford
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Justin Poklis
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Ralph Grauer
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Bogna Ignatowska-Jankowska
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Debra A. Kendall
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Dai Lu
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Aron H. Lichtman
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Keywords
Details
- Category:
- Articles
- Type:
- artykuły w czasopismach
- Published in:
-
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
no. 190,
pages 1 - 10,
ISSN: 0091-3057 - Language:
- English
- Publication year:
- 2020
- Bibliographic description:
- Olszewska T., Mohammed M., Donvito G., Moncayo L., Swafford A., Poklis J., Grauer R., Ignatowska-Jankowska B., Kendall D., Lu D., Lichtman A.: In vivoevaluation of the CB1allosteric modulator LDK1258 reveals CB1-receptor independent behavioral effects// PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR -Vol. 190, (2020), s.1-10
- DOI:
- Digital Object Identifier (open in new tab) 10.1016/j.pbb.2019.172840
- Verified by:
- Gdańsk University of Technology
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