Acs Chem Neurosci
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Low-voltage-activated (T-type) calcium channels are important regulators of the transmission of nociceptive information in the primary afferent pathway and finding ligands that modulate these channels is a key focus of the drug discovery field. Recently, we characterized a set of novel compounds with mixed cannabinoid receptor/T-type channel blocking activity and examined their analgesic effects in animal models of pain. Here, we have built on these previous findings and synthesized a new series of small organic compounds. ⋯ Compound 9 was efficacious in mediating analgesia in mouse models of acute inflammatory pain and in reducing tactile allodynia in the partial nerve ligation model. This compound was shown to be ineffective in Cav3.2 T-type calcium channel null mice at therapeutically relevant concentrations, and it caused no significant motor deficits in open field tests. Taken together, our data reveal a novel class of compounds whose physiological and therapeutic actions are mediated through block of Cav3.2 calcium channels.
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Amyloidopathic disorders such as Alzheimer's disease present symptomology years after the entrenchment of amyloidogenic imbalance. The pathologic α-helix → β-strand conversion of amyloid β(1-42) and amyloid β(1-40) peptides causes neuronal death in the vicinity. Symptomology often presents only after significant neurodegeneration. ⋯ The technique was found useful for monitoring retinal and brain amyloidopathy in an ongoing preclinical anti-AD study, attesting to the technique's sensitivity and specificity. Interestingly, the technique was found applicable not just to excised brain tissue but also to isolated mouse retina. With the retina being heralded widely as a (diagnostic) extension of the CNS and retinal amyloidopathy occurring well before that in the brain, this development raises a possibility for the first direct retinal imaging diagnosis of early asymptomatic Alzheimer's disease.