Peripheral CB1 Blockade
Inversago Pharma Inc. is focused on the development of peripherally-acting CB1 receptor (CB1) inverse agonists for the treatment of diabetic nephropathy, NASH, type 1 diabetes and Prader-Willi Syndrome.
While previous generation of centrally-acting CB1 inhibitors presented safety concerns, the therapeutic relevance of peripheral CB1 pathway is still strongly supported by comprehensive scientific evidence and remains to be fully exploited.
CB1 receptor world expert Dr George Kunos from US NIH has extensively demonstrated that peripherally-acting CB1 blockade provides an equivalent therapeutic potential to treat metabolic conditions such as obesity/NASH/T2D and fibrosis (liver and lung), without targeting central CB1 receptors.
See also references 1 to 6 at bottom of the page.
Mechanism of Action of Peripheral CB1 Blockade
The Endocannabinoid System
CB1 Receptors: Signaling the Brain from the Periphery
The endocannabinoid system is responsible for both homeostasis and equilibrium of the human metabolism. It is involved in regulating several pathways linked to energy intake, reserves and overall expenditure. To do so, the cannabinoid-1 receptor (CB1) may be activated and deactivated such that it impacts many metabolic pathways involving several enzymes and proteins, e.g. leptin, insulin and ghrelin.
While the highest density of CB1 receptors are located in the brain, most cells outside of the central nervous system (hepatocytes, β-cells, adipocytes, myocytes, epithelial cells of the GI tract, etc.) also express the CB1 receptor.
The peripheral endocannabinoid system is now recognized as an important driver in the multi-indication efficacy observed with first generation CB1 antagonists like rimonabant. As such, a safe and potent CB1 inhibitor has the potential to block or reverse (inverse agonize) the biological processes induced by their activation and treat several metabolic indications.
CB1 Inverse Agonists
A molecule binding to the CB1 receptor and activating a biological response (e.g.: seek food (increased appetite), slow down metabolism / gastric transit and reduce energy expenditure). Activation of the CB1 receptors is also involved in fibrogenesis.
CB1 Inverse Agonist
These types of molecules inhibit the signal induced by the CB1 agonist, and even reverse its biological response (e.g.: no signal to seek food, signal to increase energy expenditure and speed up metabolism at rest, prevent fibrogenesis or even reverse fibrogenesis).
1. Cinar R, Iyer MR, Liu Z, et al. Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis. JCI Insight. 2016;1(11):e87336. dx.doi.org/10.1172/jci.insight.87336
2. Cinar R, Gochuico BR, Iyer MR, et al. Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis. JCI Insight. 2017;2(8):e92281. doi.org/10.1172/jci.insight.92281
3. Bowles NP, Karatsoreos IN, Li X, et al. A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome. Proc Natl Acad Sci. 2015;112(1):285-290. dx.doi.org/10.1073/pnas.1421420112
4. Cinar R, Iyer MR, Kunos G. The therapeutic potential of second and third generation CB1R antagonists. Pharmacol Ther. 2020;208:1-24.
5. Liu Z, Iyer MR, Godlewski G, et al. Functional Selectivity of a Biased Cannabinoid-1 Receptor (CB1R) Antagonist. ACS Pharmacol Transl Sci. Published online April 8, 2021. pubs.acs.org/doi/abs/10.1021/acsptsci.1c00048
6. Cinar R, Iyer MR, Kunos G. Dual inhibition of CB 1 R and iNOS as a potential novel approach to the pharmacological management of acute and long COVID‐19. Br J Pharmacol. Published online March 26, 2021:bph.15461. doi:10.1111/bph.15461
7. Knani et al., Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syndrome, Mol. Met., (2016) 5 1187-1199. https://ncbi.nlm.nih.gov/pmc/articles/PMC5123200/