Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor

FA Pamplona, J Ferreira… - Proceedings of the …, 2012 - National Acad Sciences
FA Pamplona, J Ferreira, O Menezes de Lima Jr, FS Duarte, AF Bento, S Forner
Proceedings of the National Academy of Sciences, 2012National Acad Sciences
Allosteric modulation of G-protein–coupled receptors represents a key goal of current
pharmacology. In particular, endogenous allosteric modulators might represent important
targets of interventions aimed at maximizing therapeutic efficacy and reducing side effects of
drugs. Here we show that the anti-inflammatory lipid lipoxin A4 is an endogenous allosteric
enhancer of the CB1 cannabinoid receptor. Lipoxin A4 was detected in brain tissues, did not
compete for the orthosteric binding site of the CB1 receptor (vs. 3H-SR141716A), and did …
Allosteric modulation of G-protein–coupled receptors represents a key goal of current pharmacology. In particular, endogenous allosteric modulators might represent important targets of interventions aimed at maximizing therapeutic efficacy and reducing side effects of drugs. Here we show that the anti-inflammatory lipid lipoxin A4 is an endogenous allosteric enhancer of the CB1 cannabinoid receptor. Lipoxin A4 was detected in brain tissues, did not compete for the orthosteric binding site of the CB1 receptor (vs. 3H-SR141716A), and did not alter endocannabinoid metabolism (as opposed to URB597 and MAFP), but it enhanced affinity of anandamide at the CB1 receptor, thereby potentiating the effects of this endocannabinoid both in vitro and in vivo. In addition, lipoxin A4 displayed a CB1 receptor-dependent protective effect against β-amyloid (1–40)-induced spatial memory impairment in mice. The discovery of lipoxins as a class of endogenous allosteric modulators of CB1 receptors may foster the therapeutic exploitation of the endocannabinoid system, in particular for the treatment of neurodegenerative disorders.
National Acad Sciences