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.
Retinol-binding protein 4 (RBP4) serves as a transporter for all-trans-retinol (1) in the blood, and it has been proposed to act as an adipokine. Elevated plasma levels of the protein have been linked *
Accumulation
of cytotoxic lipofuscin bisretinoids may contribute to atrophic age-related macular
degeneration (AMD) pathogenesis. Retinal bisretinoid synthesis depends
on the influx of serum all-trans-retinol (1) delivered via a tertiary retinol binding protein 4 (RBP4)–transthyretin
(TTR)–retinol complex. We previously identified selective RBP4
antagonists that dissociate circulating RBP4–TTR–retinol
complexes, reduce serum RBP4 levels, and inhibit bisretinoid synthesis
in models of enhanced retinal lipofuscinogenesis. However, the release
of TTR by selective RBP4 antagonists may be associated with TTR tetramer
destabilization and, potentially, TTR amyloid formation. We describe
herein the identification of bispecific RBP4 antagonist–TTR
tetramer kinetic stabilizers. Standout analogue (±)-44 possesses suitable potency for both targets, significantly lowers
mouse plasma RBP4 levels, and prevents TTR aggregation in a gel-based
assay. This new class of bispecific compounds may be especially important
as a therapy for dry AMD patients who have another common age-related
comorbidity, senile systemic amyloidosis, a nongenetic disease associated
with wild-type TTR misfolding.
Glycine
neurotransmission in the dorsal horn of the spinal cord
plays a key role in regulating nociceptive signaling, but in chronic
pain states reduced glycine neurotransmission is associated with the
development of allodynia and hypersensitivity to painful stimuli.
This suggests that restoration of glycine neurotransmission may be
therapeutic for the treatment of chronic pain. Glycine transporter
2 inhibitors have been demonstrated to enhance glycine neurotransmission
and provide relief from allodynia in rodent models of chronic pain.
In recent years, photoswitchable compounds have been developed to
provide the possibility of controlling the activity of target proteins
using light. In this study we have developed a photoswitchable noncompetitive
inhibitor of glycine transporter 2 that has different affinities for
the transporter at 365 nm compared to 470 nm light.
Numerous research groups have developed GlyT-1 inhibitors in the pursuit of providing a novel antipsychotic treatment for schizophrenia. Despite multiple compounds advancing into clinical trials, a GlyT-1 inhibitor has yet to emerge to treat patients. However, the approach remains heavily investigated as it presents potential therapeutic utility for several other CNS and non-CNS-related indications. Areas covered: This review discusses various GlyT-1 inhibitor chemotypes identified and provides an overview of patent applications filed and published during the period of 2011-2016. The review largely focuses on composition of matter patent applications, although two recently disclosed method of use patents are discussed. Clinical reports are also disseminated. Expert opinion: Mounting clinical failures with schizophrenic patients have blunted enthusiasm for GlyT-1 inhibition as an approach to treat the disease. However, research in the area remains quite active, as therapeutic potential for several additional indications has emerged. There are numerous and diverse GlyT-1 chemotypes now available that exhibit differentiating modes of binding and ligand-target binding kinetics, and this rich diversity of chemical matter may help further elucidate the target's pharmacological role in various indications and lead to the identification of a compound with optimal properties that may someday become a drug.
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