Biased Agonism and Biased Allosteric Modulation at the CB₁Cannabinoid Receptor

Abstract

CB 1 cannabinoid receptors (CB 1 Rs) are attractive therapeutic targets for numerous central nervous system disorders. However, clinical application of cannabinoid ligands has been hampered owing to their adverse on-target effects. Ligand-biased signaling from, and allosteric modulation of, CB 1 Rs offer pharmacological approaches that may enable the development of improved CB 1 R drugs, through modulation of only therapeutically desirable CB 1 R signaling pathways. There is growing evidence that CB 1 Rs are subject to ligand-biased signaling and allosterism. Therefore, in the present study, we quantified ligand-biased signaling and allosteric modulation at CB 1 Rs. Cannabinoid agonists displayed distinct biased signaling profiles at CB 1 Rs. For instance, whereas 2-arachidonylglycerol and WIN55,212-2 [(R)- (1) [5-chloro-3-ethyl-1H-indole-2-carboxylic acid [2-(4-piperidin-1-yl-phenyl)ethyl]amide] displayed biased allosteric effects by blocking cAMP inhibition mediated by all cannabinoid ligands tested, at the same time having little or no effect on ERK1/2 phosphorylation mediated by a subset of these ligands. Org27569 also displayed negative binding cooperativity with [however, it had minimal effects on binding of cannabinoid agonists. Furthermore, we highlight the need to validate the reported allosteric effects of the endogenous ligands lipoxin A4 and pregnenolone at CB 1 Rs. Pregnenolone but not lipoxin A4 displaced [ 3 H]SR141716A, but there was no functional interaction between either of these ligands and cannabinoid agonists. This study demonstrates an approach to validating and quantifying ligand-biased signaling and allosteric modulation at CB 1 Rs, revealing ligand-biased "fingerprints" that may ultimately allow the development of improved CB 1 R-targeted therapies.

Biased Type 1 Cannabinoid Receptor Signaling Influences Neuronal Viability in a Cell Culture Model of Huntington Disease

“…Signaling bias could be exploited for enhancement of CB 1 function in HD, at the same time limiting detrimental adverse on-target effects (Laprairie et al, 2014). Cannabinoids display signaling bias (Laprairie et al, 2014;Khajehali et al, 2015). Endocannabinoids acting at CB 1 are Ga i/o -biased, whereas THC and CP are b-arrestinbiased in STHdh Q7/Q7 cells (Laprairie et al, 2014).…”

Does cannabidiol have a role in the treatment of schizophrenia?

“…A recent in vitro study has suggested another mechanism of action of CBD could involve negative allosteric modulation (NAM) at the CB1 receptor (Laprairie et al, 2015) but we have not been able to observe NAM effects at CB1 receptors when investigating CB1 receptor agonists with other NAMs (Khajehali et al, 2015). Importantly, this mechanism has not been validated in vivo.…”

Functional selectivity – chance for better and safer drugs?

“…functionally selective agonists. Biased agonism, has been identified for many therapeutically important GPCRs such as α 1 -and β-adrenergic receptors [16,[23][24][25], μ-opioid receptors (MOR) [26,27], cannabinoid receptors [28,29], D 2L and D 1 dopamine receptors [30][31][32][33], serotonin receptors [17,34,35], chemokine receptor CCR7 [36,37], gonadotropin-releasing hormone receptors [38,39], parathyroid hormone 1 receptors (PTH1R) [40,41], angiotensin 1A (AT 1A ) receptors [42] or MC4 melanocortin receptors [43].…”