In vivo evaluation of the CB1 allosteric modulator LDK1258 reveals CB1-receptor independent behavioral effects.
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.
['Mustafa|Mohammed|M|', 'Donvito|Giulia|G|', 'Moncayo|Lauren|L|', 'Swafford|Amelia|A|', 'Poklis|Justin|J|', 'Grauer|Ralph|R|', 'Olszewska|Teresa|T|', 'Ignatowska-Jankowska|Bogna|B|', 'Kendall|Debra A|DA|', 'Lu|Dai|D|', 'Lichtman|Aron H|AH|']
D000494:Allosteric Regulation D000581:Amidohydrolases D000700:Analgesics D000818:Animals D001067:Appetite Depressants D001095:Arachidonic Acids D001522:Behavior, Animal D063386:Cannabinoid Receptor Agonists D063387:Cannabinoid Receptor Antagonists D002853:Chromatography, Liquid D003511:Cyclohexanols D004195:Disease Models, Animal D063388:Endocannabinoids D005260:Female D008124:Locomotion D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D009437:Neuralgia D053284:Polyunsaturated Alkamides D043884:Receptor, Cannabinoid, CB1 D000077285:Rimonabant D053719:Tandem Mass Spectrometry
Allosteric modulator Neuropathic pain Anandamide Drug discrimination CB(1) receptor CP55 940 Cannabinoid Rimonabant