64907-20-6

Upstream product

• 2140-46-7 25-hydroxychlolesterol 

Relevant academic research and scientific papers

GPR183-oxysterol axis in spinal cord contributes to neuropathic pain

Neuropathic pain is a debilitating public health concern for which novel non-narcotic therapeutic targets are desperately needed. Using unbiased transcriptomic screening of the dorsal horn spinal cord after nerve injury we have identified that Gpr183 (Epstein-Barr virus-induced gene 2) is upregulated after chronic constriction injury (CCI) in rats. GPR183 is a chemotactic receptor known for its role in the maturation of B cells, and the endogenous ligand is the oxysterol 7a,25-dihydrox-ycholesterol (7a,25-OHC). The role of GPR183 in the central nervous system is not well characterized, and its role in pain is unknown. The profile of commercially available probes for GPR183 limits their use as pharmacological tools to dissect the roles of this receptor in pathophysiological settings. Using in silico modeling, we have screened a library of 5 million compounds to identify several novel small-molecule antagonists of GPR183 with nanomolar potency. These compounds are able to antagonize 7a,25-OHC-induced calcium mobilization in vitro with IC50 values below 50 nM. In vivo intrathecal injections of these antagonists during peak pain after CCI surgery reversed allodynia in male and female mice. Acute intrathecal injection of the GPR183 ligand 7a,25-OHC in na?ve mice induced dose-dependent allodynia. Importantly, this effect was blocked using our novel GPR183 antagonists, suggesting spinal GPR183 activation as pronociceptive. These studies are the first to reveal a role for GPR183 in neuropathic pain and identify this receptor as a potential target for therapeutic intervention. SIGNIFICANCE STATEMENT We have identified several novel GPR183 antagonists with nanomolar potency. Using these antagonists, we have demonstrated that GPR183 signaling in the spinal cord is pronociceptive. These studies are the first to reveal a role for GPR183 in neuropathic pain and identify it as a potential target for therapeutic intervention.

Inhibitory effect of oxygenated cholestan-3-ol derivatives on the growth of Mycobacterium tuberculosis

A variety of cholestan-3-ol derivatives, which are oxygenated at different positions of the steroid ring system, were prepared and tested for their inhibition of the Mycobacterium tuberculosis H37Rv strain. Several compounds showed significant antitubercular activities with MIC90 values in the range 4-8 μM and low or non-detectable toxicity against mammalian cells.

Regio- and stereospecific synthesis of cholesterol derivatives and their hormonal activity in Caenorhabditis elegans

Cholesterol is essential for the survival of the nematode Caenorhabditis elegans. Recent studies have demonstrated that cholesterol derivatives regulate two processes in the life cycle of worms: controlling molting and inducing a specialized non-feeding larval stage. However, the chemical structure of the cholesterol-derived signalling molecules for these or any other functions has not yet been identified. Herein, we describe the regio- and stereospecific synthesis of a number of cholesterol derivatives. The lithium-ammonia reduction of 4-cholesten-3-one was utilized to develop a general method for the introduction of diverse functional groups at C-4α of 5α-cholestan- 3β-ol. Stereoselective functionalization at C-7 was achieved starting from 7-ketocholesterol derivatives. 6-Keto-5α-cholestan-3β-ol was utilized for specific functionalizations at C-6 and C-7. The structure-activity relationships of the different cholesterol derivatives have been investigated by feeding worms of different genetic background with these compounds. Our study is the first step in assigning the relationships of hormonal activity in C. elegans on the substitution at different positions of cholesterol. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.