Dual-targeting peripheral CB1 receptors (CB1R) and iNOS by novel hybrid compound improves anti-fibrotic efficacy and safety in liver fibrosis

Wednesday, September 24, 2014 — Poster Session IV
10:00 a.m. –12:00 p.m.	FAES Academic Center	NIAAA	CHEMBIO-1

* FARE Award Winner

Authors

• R Cinar
• M Iyer
• Z Liu
• Z Cao
• T Jourdan
• G Szanda
• G Godlewski
• J Liu
• P Pacher
• K Rice
• G Kunos

Abstract

Endocannabinoids acting via CB1R are profibrotic in liver, whereas the CB1R antagonist rimonabant (Ki 3 nM) mitigates liver fibrosis, but it also causes psychiatric side effects by blocking CB1R in the brain. Increased activity of nitric oxide synthase (iNOS) is known to promote fibrosis. We tested whether dual targeting of peripheral CB1R and iNOS for inhibition increases anti-fibrotic efficacy over single targeting these molecules, and is also safer than targeting CB1R globally. (S)-MRI-1569 selectively blocks peripheral CB1R (Ki 9 nM) due to its limited brain penetrance (plasma:brain ratio 0.03 vs 0.9 for rimonabant), and also acts as prodrug or parent drug to directly inhibit iNOS activity in vitro by 48% and 37% at 1 µM, whereas 1 μM rimonabant does not affect iNOS activity. (S)-MRI-1569 was more efficacious than rimonabant in mitigating liver fibrosis as quantified by Sirius red and by fibronectin, procollagen-1 and α-SMA gene expression in BDL and CCl4-induced fibrosis. In addition, CCl4-induced increase in iNOS immunostaining was attenuated by (S)-MRI-1569 but not by rimonabant. Furthermore, rimonabant, but not (S)-MRI-1569, was anxiogenic after 4 weeks of treatment. Dual-purpose CB1R/iNOS inhibitors can provide a novel form of pharmacotherapy for liver fibrosis with improved efficacy and safety.

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