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Nanomolar TLR4 Antagonist CIAC101 Derived from (+)-Naltrexone Blocks Microglial Activation and Methamphetamine Addiction.
Gao J, Lin C, Deng L, Wang H, Wang X. Gao J, et al. J Med Chem. 2025 Dec 11;68(23):25469-25484. doi: 10.1021/acs.jmedchem.5c02596. Epub 2025 Nov 20. J Med Chem. 2025. PMID: 41265859
Neuroimmune activation via Toll-like receptor 4 (TLR4) contributes to the pathophysiology of substance use disorders. Although (+)-naltrexone can antagonize TLR4 without engaging classical opioid receptors, its modest potency limits translational potential. T …
Neuroimmune activation via Toll-like receptor 4 (TLR4) contributes to the pathophysiology of substance use disorders. Although (+)- …
Structure-Activity Relationships of (+)-Naltrexone-Inspired Toll-like Receptor 4 (TLR4) Antagonists.
Selfridge BR, Wang X, Zhang Y, Yin H, Grace PM, Watkins LR, Jacobson AE, Rice KC. Selfridge BR, et al. J Med Chem. 2015 Jun 25;58(12):5038-52. doi: 10.1021/acs.jmedchem.5b00426. Epub 2015 Jun 5. J Med Chem. 2015. PMID: 26010811 Free PMC article.
Activation of Toll-like receptors has been linked to neuropathic pain and opioid dependence. (+)-Naltrexone acts as a Toll-like receptor 4 (TLR4) antagonist and has been shown to reverse neuropathic pain in rat studies. We designed and synthesized compounds based on …
Activation of Toll-like receptors has been linked to neuropathic pain and opioid dependence. (+)-Naltrexone acts as a Toll-like recep …
Experimental autoimmune encephalopathy (EAE)-induced hippocampal neuroinflammation and memory deficits are prevented with the non-opioid TLR2/TLR4 antagonist (+)-naltrexone.
Kwilasz AJ, Todd LS, Duran-Malle JC, Schrama AEW, Mitten EH, Larson TA, Clements MA, Harris KM, Litwiler ST, Wang X, Van Dam AM, Maier SF, Rice KC, Watkins LR, Barrientos RM. Kwilasz AJ, et al. Behav Brain Res. 2021 Jan 1;396:112896. doi: 10.1016/j.bbr.2020.112896. Epub 2020 Sep 6. Behav Brain Res. 2021. PMID: 32905811 Free PMC article.
Previously, we have shown that toll-like receptor 4 (TLR4) antagonists, such as (+)-naltrexone [(+)-NTX], block neuropathic pain and associated spinal inflammation in rats. ...These findings suggest that (+)-NTX may exert therapeutic effects on memory function by da …
Previously, we have shown that toll-like receptor 4 (TLR4) antagonists, such as (+)-naltrexone [(+)-NTX], block neuropathic pa …
Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4.
Bachtell R, Hutchinson MR, Wang X, Rice KC, Maier SF, Watkins LR. Bachtell R, et al. CNS Neurol Disord Drug Targets. 2015;14(6):692-9. doi: 10.2174/1871527314666150529132503. CNS Neurol Disord Drug Targets. 2015. PMID: 26022268 Free PMC article. Review.
Indeed, selective pharmacological blockade of TLR4 activation, such as with the non-opioid TLR4 antagonist (+)-naltrexone, suppresses a number of indices of drug reward/reinforcement. ...Genetic disruption of TLR4 signaling recapitulates the effects of …
Indeed, selective pharmacological blockade of TLR4 activation, such as with the non-opioid TLR4 antagonist (+)-naltrexone …
Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4).
Hutchinson MR, Zhang Y, Brown K, Coats BD, Shridhar M, Sholar PW, Patel SJ, Crysdale NY, Harrison JA, Maier SF, Rice KC, Watkins LR. Hutchinson MR, et al. Eur J Neurosci. 2008 Jul;28(1):20-9. doi: 10.1111/j.1460-9568.2008.06321.x. Eur J Neurosci. 2008. PMID: 18662331 Free PMC article.
The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic nerve chronic constriction injury (CCI). Established neuropathic pain was reversed by intrathecally delivered TLR4 receptor antagoni …
The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic …
Stereochemistry and innate immune recognition: (+)-norbinaltorphimine targets myeloid differentiation protein 2 and inhibits toll-like receptor 4 signaling.
Zhang X, Peng Y, Grace PM, Metcalf MD, Kwilasz AJ, Wang Y, Zhang T, Wu S, Selfridge BR, Portoghese PS, Rice KC, Watkins LR, Hutchinson MR, Wang X. Zhang X, et al. FASEB J. 2019 Aug;33(8):9577-9587. doi: 10.1096/fj.201900173RRR. Epub 2019 Jun 4. FASEB J. 2019. PMID: 31162938 Free PMC article.
Naltrexone is one of the rare TLR4 antagonists with good blood-brain barrier permeability and showing no stereoselectivity for TLR4. ...Interestingly, (+)-norbinaltorphimine [(+)-1] showed 25 times better TLR4 antagonist activity than naltrexone …
Naltrexone is one of the rare TLR4 antagonists with good blood-brain barrier permeability and showing no stereoselectivity for …
(+)-Naltrexone is neuroprotective and promotes alternative activation in the mouse hippocampus after cardiac arrest/cardiopulmonary resuscitation.
Grace PM, Shimizu K, Strand KA, Rice KC, Deng G, Watkins LR, Herson PS. Grace PM, et al. Brain Behav Immun. 2015 Aug;48:115-22. doi: 10.1016/j.bbi.2015.03.005. Epub 2015 Mar 13. Brain Behav Immun. 2015. PMID: 25774010 Free PMC article.
Classical microgliosis in the CA1 region may contribute to neuronal death, yet the role of a key activation receptor Toll Like Receptor 4 (TLR4) has not been previously investigated for such neuronal death after CA/CPR. We show that (+)-naltrexone was neuroprotectiv …
Classical microgliosis in the CA1 region may contribute to neuronal death, yet the role of a key activation receptor Toll Like Receptor 4 ( …
Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4.
Wang X, Zhang Y, Peng Y, Hutchinson MR, Rice KC, Yin H, Watkins LR. Wang X, et al. Br J Pharmacol. 2016 Mar;173(5):856-69. doi: 10.1111/bph.13394. Epub 2016 Feb 4. Br J Pharmacol. 2016. PMID: 26603732 Free PMC article.
However, how these agents modulate TLR4 signalling is not clear. Here, we have elucidated the molecular mechanism of (+)-naltrexone and (+)-naloxone on TLR4 signalling. ...CONCLUSIONS AND IMPLICATIONS: (+)-Naltrexone and (+)-naloxone were TRIF-IFN regu …
However, how these agents modulate TLR4 signalling is not clear. Here, we have elucidated the molecular mechanism of (+)-naltrexon …
A role for neuroimmune signaling in a rat model of Gulf War Illness-related pain.
Lacagnina MJ, Li J, Lorca S, Rice KC, Sullivan K, O'Callaghan JP, Grace PM. Lacagnina MJ, et al. Brain Behav Immun. 2021 Jan;91:418-428. doi: 10.1016/j.bbi.2020.10.022. Epub 2020 Oct 27. Brain Behav Immun. 2021. PMID: 33127584 Free PMC article.
Additionally, Toll-like receptor 4 (TLR4) mRNA was elevated in the lumbar dorsal spinal cord, while IL-1beta and IL-6 were elevated in the lumbar dorsal spinal cord, DRG, and gastrocnemius muscle. Demonstrating a casual role for such neuroinflammatory signaling, allodynia …
Additionally, Toll-like receptor 4 (TLR4) mRNA was elevated in the lumbar dorsal spinal cord, while IL-1beta and IL-6 were elevated i …
Release of neuronal HMGB1 by ethanol through decreased HDAC activity activates brain neuroimmune signaling.
Zou JY, Crews FT. Zou JY, et al. PLoS One. 2014 Feb 14;9(2):e87915. doi: 10.1371/journal.pone.0087915. eCollection 2014. PLoS One. 2014. PMID: 24551070 Free PMC article.
Ethanol and HMGB1 treatment increased mRNA expression of proinflammatory cytokines TNFalpha and IL-1beta as well as toll-like receptor 4 (TLR4). Targeting HMGB1 or microglial TLR4 by using siRNAs to HMGB1 and TLR4, HMGB1 neutralizing antibody, HMGB1 inhibitor …
Ethanol and HMGB1 treatment increased mRNA expression of proinflammatory cytokines TNFalpha and IL-1beta as well as toll-like receptor 4 ( …
13 results