10525-22-1Relevant articles and documents
GPR183-oxysterol axis in spinal cord contributes to neuropathic pain
Arnatt, Christopher Kent,Boehm, Terri,Braden, Kathryn,Chen, Zhoumou,D'Cunha, Napoleon,DeLeon, Chelsea,Doyle, Timothy M.,Giancotti, Luigino Antonio,Kolar, Grant R.,Latzo, Nick,McDonald, Jeffrey G.,Salvemini, Daniela,Thompson, Bonne M.,Walker, John K.
, p. 367 - 375 (2020)
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.
Oxidation of Natural Targets by Dioxiranes. 2. Direct Hydroxylation at the Side-Chain C-25 of Cholestane Derivatives and of Vitamin D3 Windaus-Grundmann Ketone
Bovicelli, Paolo,Lupattelli, Paolo,Mincione, Enrico,Prencipe, Teresa,Curci, Ruggero
, p. 5052 - 5054 (1992)
The direct, high-yield oxyfunctionalization of the side-chain C-25 of 5α-cholestan-3-one, 3β-acetoxy-5α-cholestane, and 5α,6β-Br2-3β-acetoxycholestane as well as of the vitamin D3-derived Windaus-Grundmann ketone has been achieved under mild conditions employing either dimethyldioxirane or its trifluoromethyl analogue.
Inhibitory effect of oxygenated cholestan-3-ol derivatives on the growth of Mycobacterium tuberculosis
Schmidt, Arndt W.,Choi, Taylor A.,Theumer, Gabriele,Franzblau, Scott G.,Kn?lker, Hans-Joachim
, p. 6111 - 6113 (2013)
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.
Keinan,Mazur
, p. 1020 (1978)
GPR183 ANTAGONISTS FOR THE TREATMENT OF PAIN
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Paragraph 0273; 0274, (2021/04/30)
Disclosed herein are compositions and methods for treating neuropathic pain in a subject in need thereof. Compositions disclosed herein are GPR183 antagonists. The methods include administering to a subject in need thereof a therapeutically effective amount of a GPR183 antagonist.
A 25-hydroxy cholesterol synthesis method
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Paragraph 0030; 0031, (2017/02/28)
The present invention discloses a method for synthesizing 25-hydroxy cholesterol. The method is as below: subjecting 24-dehydrocholesterol derivative as a raw material, which undergoes an addition reaction with a hydroxyl containing reagent in an organic solvent under catalysis, and then hydrolyzing the reaction product and separating to obtain 25-hydroxy cholesterol. The present invention adopts hydroxyl containing reagents such as water, formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, p-methyl benzoic acid to replace the commonly used extremely toxic reagents such as Cr reagent, Hg reagent and polyfluorinated acetone in the prior art. The raw materials of the present invention are easily available, and have low effect on environment. The operation and post treatment are convenient. Moreover, the method has the advantages of mild reaction conditions, simple operation, good selectivity, high efficiency, high yield, simple post treatment, easy product separation, less three wastes and easy industrialization.
