2-(Aminomethyl)-benzamide-based glycine transporter type-2 inhibitors

Ho, Koc-Kan; Appell, Kenneth C.; Baldwin, John J.; Bohnstedt, Adolph C.; Dong, Guizhen; Guo, Tao; Horlick, Robert A.; Islam, Khondaker; Kultgen, Steven G.; Masterson, Christopher M.; McDonald, Edward; McMillan, Kirk; Morphy, J. Richard; Rankovic, Zoran; Sundaram, Hardy; Webb, Maria L.

doi:10.1016/j.bmcl.2003.09.080

Cited by 17 publications

(5 citation statements)

References 11 publications

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“…The combination of high colocalization with GlyRs, restricted distribution within the CNS, and high expression density in the dorsal horn make GlyT-2 a very attractive target for the treatment of chronic pain. Multiple distinct chemotypes capable of inhibiting GlyT-2 with high affinity and selectivity have been reported (e.g., 7 (ALX-1393), 8 (Org-25543), 9 (NAGly), 10 (GT-0198), 11 , 12 , (±)- 13 , 14 , 15 ) (Figure ), and many of them have shown considerable potential as novel analgesics by demonstrating broad efficacy in several rodent models of acute, inflammatory, and neuropathic pain (Table ). Furthermore, GlyT-2 inhibitors have demonstrated efficacy in preclinical studies involving both acute and chronic dosing regimens.…”

Section: Glycine Transporter Inhibitionmentioning

confidence: 99%

Modulation of Glycine-Mediated Spinal Neurotransmission for the Treatment of Chronic Pain

Cioffi

2017

J. Med. Chem.

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Chronic pain constitutes a significant and expanding worldwide health crisis. Currently available analgesics poorly serve individuals suffering from chronic pain, and new therapeutic agents that are more effective, safer, and devoid of abuse liabilities are desperately needed. Among the myriad of cellular and molecular processes contributing to chronic pain, spinal disinhibition of pain signaling to higher cortical centers plays a critical role. Accumulating evidence shows that glycinergic inhibitory neurotransmission in the spinal cord dorsal horn gates nociceptive signaling, is essential in maintaining physiological pain sensitivity, and is diminished in pathological pain states. Thus, it is hypothesized that agents capable of enhancing glycinergic tone within the dorsal horn could obtund nociceptor signaling to the brain and serve as analgesics for persistent pain. This Perspective highlights the potential that pharmacotherapies capable of increasing inhibitory spinal glycinergic neurotransmission hold in providing new and transformative analgesic therapies for the treatment of chronic pain.

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Section: Glycine Transporter Inhibitionmentioning

confidence: 99%

Modulation of Glycine-Mediated Spinal Neurotransmission for the Treatment of Chronic Pain

Cioffi

2017

J. Med. Chem.

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“…GlyT2-mediated uptake is inhibited by the antidepressant amoxapine [66]. In addition, 4-benzyloxy-3,5-dimethoxy[(1-dimethylaminoacylclopentyl) methyl]-benzamide and a series of 5,5-diaryl-2-amino pentenoates have been reported to be potent inhibitors of GlyT2 [67,68].…”

Section: Box 2 Tissue Expression Subcellular Localization and Pharmac...mentioning

confidence: 99%

Glycine transporters: essential regulators of neurotransmission

Eulenburg

Armsen

Betz

et al. 2005

Trends in Biochemical Sciences

304

224

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“…BHQ- N -5HT was prepared by activating the primary alcohol with carbonyldiimidazole, then treating the resulting carbamate (MOM-BHQ-Carbonylimidazole) with TIPS-protected serotonin (5HT( O -TIPS), which was prepared as previously described (Ho, et al, 2003). Removal of first the TIPS protecting group with TBAF was followed by the MOM deprotection in acidic methanol to provide BHQ- N -5HT (Figure 2c).…”

Section: Resultsmentioning

confidence: 99%

Light-Activated Serotonin for Exploring Its Action in Biological Systems

Rea

Vandenberg

Ball

et al. 2013

Chemistry & Biology

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Summary Serotonin (5-HT) is a neuromodulator involved in regulating mood, appetite, memory, learning, pain, and establishment of left-right (LR) asymmetry in embryonic development. To explore the role of 5-HT in a variety of physiological contexts, we have created two forms of “caged” 5-HT, BHQ-O-5HT and BHQ-N-5HT. When exposed to 365- or 740-nm light, BHQ-O-5HT releases 5-HT through 1- or 2-photon excitation, respectively. BHQ-O-5HT mediated changes in neural activity in cultured primary sensory neurons from mouse and the trigeminal ganglion and optic tectum of intact zebrafish larvae in the form of high amplitude spiking in response to light. In Xenopus laevis embryos, 5-HT released from BHQ-O-5HT upon exposure to light increased the occurrence of LR patterning defects. Maximal rates of LR defects were observed when 5-HT was released at stage 5 compared to stage 8. These experiments show the potential for BHQ-caged serotonins in studying 5-HT-regulated physiological processes.

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2-(Aminomethyl)-benzamide-based glycine transporter type-2 inhibitors

Cited by 17 publications

References 11 publications

Modulation of Glycine-Mediated Spinal Neurotransmission for the Treatment of Chronic Pain

Modulation of Glycine-Mediated Spinal Neurotransmission for the Treatment of Chronic Pain

Glycine transporters: essential regulators of neurotransmission

Light-Activated Serotonin for Exploring Its Action in Biological Systems

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