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. Likewis

SUBMITTER: Mustafa M 

PROVIDER: S-EPMC8791624 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature