|(I most often skip posting new agonist or antagonist chemistries, as there is a constant stream of new ones. But the first abstract has the in vivo kicker. The second abstract describes an animal injury model, and some may want to stop reading short of it.)|
J Med Chem. 2017 Jul 20. doi: 10.1021/acs.jmedchem.7b00724. [Epub ahead of print]
Amidoalkylindoles as Potent and Selective Cannabinoid Type 2 Receptor Agonists with In Vivo Efficacy in a Mouse Model of Multiple Sclerosis.
Shi Y, Duan YH, Ji YY, Wang ZL, Wu YR, Gunosewoyo H, Xie XY, Chen JZ, Yang F, Li J, Tang J, Xie X, Yu LF.
Selective CB2 agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases without psychiatric side effects mediated by the CB1 receptor. We carried out a rational optimization of a black market designer drug SDB-001 that led to the identification of potent and selective CB2 agonists. A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles resulted in potent CB2 antagonists (27 or 28, IC50 = 16-28 nM). Replacement of the amidoalkyls from 3-position to the 2-position of the indole ring dramatically increased the agonist selectivity on the CB2 over CB1 receptor. Particularly, compound 57 displayed a potent agonist activity on the CB2 receptor (EC50 = 114-142 nM) without observable agonist or antagonist activity on the CB1 receptor. Furthermore, 57 significantly alleviated the clinical symptoms and protected the murine central nervous system from immune damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis.
Brain Res. 2017 Jul 14. pii: S0006-8993(17)30268-8. doi: 10.1016/j.brainres.2017.06.020. [Epub ahead of print]
The synthetic cannabinoid WIN55212-2 ameliorates traumatic spinal cord injury via inhibition of GAPDH/Siah1 in a CB2-receptor dependent manner.
Su BX1, Chen X2, Huo J1, Guo SY3, Ma R4, Liu YW5.
Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Department of Anesthesiology, Shaanxi Provincial People's Hospital, Xi'an 710068, China.
Department of Pharmaceutics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: firstname.lastname@example.org.
Institute of Orthopedics, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
The essential role of GAPDH/Siah1 signaling pathway in the pathogenesis of various injurious conditions such as traumatic spinal cord injury (SCI) has been gradually recognized. However, the drugs targeting this signaling pathway are still lacking. The endocannabinoid system, including its receptors (CB1 and CB2), act as neuroprotective and immunomodulatory modulators in SCI. WIN55212-2, an agonist for CB1 and CB2 receptors, has been demonstrated with anti-inflammatory and anti-apoptotic effects in multiple neurological diseases. Therefore, the present study aimed to investigate whether WIN55212-2 could promote functional recovery after traumatic SCI via inhibition of the GAPDH/Siah1 signaling. The traumatic SCI was induced by dropping a 10-g impactor from 25 mm on the dorsal surface of T9 and T10. Our results showed that WIN55212-2 alleviated the activation of GAPDH/Siah1 signaling pathway after SCI, as indicated by the reduction in GAPDH nuclear expression, GAPDH-Siah1 complex formation and iNOS protein expression. Furthermore, WIN55212-2 reduced apoptosis, production of IL-1ß and TNF-a and activation of NF-?B signaling in the spinal cord after SCI. The behavioral tests showed that WIN55212-2 improved the functional recovery after traumatic SCI as indicated by sustained increase in the locomotor scores. However, these neuroprotective effects of WIN55212-2 were blocked in the presence of the combined treatment of AM630 (an antagonist of CB2) rather than AM251 (an antagonist of CB1). In conclusion, our study indicates that, WIN55212-2 improves the functional recovery after SCI via inhibition of GAPDH/Siah1 cascades in a CB2 receptor dependent manner, indicative of its therapeutic potential for traumatic SCI or other traumatic conditions.