Discovery and structure-activity relationships study of positive allosteric modulators of the M muscarinic acetylcholine receptor.

The M muscarinic acetylcholine receptor (mAChR) is a member of the family of mAChRs, which are associated with a variety of physiological functions including the contraction of various smooth muscle tissues, stimulation of glandular secretion, and regulation of a range of cholinergic processes in the central nerve system. We report here the discovery and a comprehensive structure--activity relationships (SARs) study of novel positive allosteric modulators (PAMs) of the M mAChR through a high throughput screening (HTS) campaign. Compound 9 exhibited potent in vitro PAM activity towards the M mAChR and significant enhancement of muscle contraction in a concentration-dependent manner when applied to isolated smooth muscle strips of rat bladder.

New index of pain triggered by spinal activation of voltage-dependent sodium channels.

Voltage-dependent sodium channels (VDSCs) are crucial for pain generation. Here, to develop a new behavioral index of pain induced by spinal VDSC activation, we examined whether intrathecal veratridine injection produced nociceptive behavior. Intrathecal injection of the VDSC opener veratridine in mice dose-dependently induced nociceptive responses, with response times subsequently reduced by administration of morphine or pregabalin.

Spinal mechanism of standard analgesics: evaluation using mouse models of allodynia.

Spinal neurotransmission plays an important role in the perception of pain signaling. In the present study, we investigated the spinal anti-nociceptive mechanism of current standard analgesics in mouse models of tactile allodynia induced by intrathecal administration of N-methyl-D-aspartic acid (NMDA), prostaglandin E2 (PGE2), and bicuculline. NMDA-induced allodynia is induced by postsynaptic NMDA receptor activation, while PGE2-induced allodynia is triggered by the enhancement of presynaptic glutamate release via EP1 receptor activation.

The involvement of aldose reductase in alterations to neurotrophin receptors and neuronal cytoskeletal protein mRNA levels in the dorsal root ganglion of streptozotocin-induced diabetic rats.

Dorsal root ganglia (DRG) are recognized as one of the organs which are damaged in peripheral sensory diabetic neuropathy. In an experimental animal model, the alteration of the mRNA expression level of neurotrophins, their receptors and neuronal cytoskeletal protein have been reported. In this study, we examined whether these changes are improved by treatment with the aldose reductase inhibitor, zenarestat, in early-stage diabetic neuropathy of streptozotocin (STZ)-induced diabetic rats.

Pharmacological characterization of standard analgesics on mechanical allodynia in streptozotocin-induced diabetic rats.

The present study was designed to investigate the anti-allodynic effects of current analgesic agents, such as pregabalin, amitriptyline, mexiletine, morphine, and diclofenac, in a rat model of streptozotocin (STZ)-induced diabetic neuropathy. Diabetic rats developed a sustained decrease in withdrawal threshold response to the von Frey test within 8 weeks after a single injection of STZ (45 mg/kg, i.v.

Thirteen-month inhibition of aldose reductase by zenarestat prevents morphological abnormalities in the dorsal root ganglia of streptozotocin-induced diabetic rats.

The dorsal root ganglia (DRG) have been identified as the target tissue in diabetic somatosensory neuropathy. It has been reported that, in the chronically diabetic state, DRG sensory neurons may undergo morphological changes. In this study, we examined the effect of zenarestat, an aldose reductase inhibitor, on the morphological derangement of the DRG and the sural nerve of streptozotocin-induced diabetic rats (STZ rats) over a 13-month period.