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This study was conducted to identify the characteristic pharmacological features of GT-0198 that is phenoxymethylbenzamide derivatives. GT-0198 inhibited the function of glycine transporter 2 (GlyT2) in human GlyT2-expressing HEK293 cells and did not bind various major transporters or receptors of neurotransmitters in a competitive manner. Thus, GT-0198 is considered to be a comparatively selective GlyT2 inhibitor. Intravenous, oral, and intrathecal injections of GT-0198 decreased the pain-related response in a model of neuropathic pain with partial sciatic nerve ligation. This result suggests that GT-0198 has an analgesic effect. The analgesic effect of GT-0198 was abolished by the intrathecal injection of strychnine, a glycine receptor antagonist. Therefore, GT-0198 is considered to exhibit its analgesic effect via the activation of a glycine receptor by glycine following presynaptic GlyT2 inhibition in the spinal cord. In summary, GT-0198 is a structurally novel GlyT2 inhibitor bearing a phenoxymethylbenzamide moiety with in vivo efficacy in behavioral models of neuropathic pain.

The activation of cholinergic pathways by nicotine elicits various physiological and pharmacological effects in mammals. For example, the stimulation of nicotinic acetylcholine receptors (nAChRs) leads to an antinociceptive effect. However, it remains to be elucidated which subtypes of nAChR are involved in the antinociceptive effect of nicotine on nerve injury-induced allodynia and the underlying cascades of the nAChR-mediated antiallodynic effect. In this study, we attempted to characterize the actions of nicotine at the spinal level against mechanical allodynia in an animal model of neuropathic pain, tibial nerve transection (TNT) in rats. It was found that the intrathecal injection of nicotine, RJR-2403, a selective alpha4beta2 nAChR agonist, and choline, a selective alpha7 nAChR agonist, produced an antinociceptive effect on the TNT-induced allodynia. The actions of nicotine were almost completely suppressed by pretreatment with mecamylamine, a non-selective nicotinic antagonist, or dihydro-beta-erythroidine, a selective alpha4beta2 nAChR antagonist, and partially reversed by pretreatment with methyllycaconitine, a selective alpha7 nAChR antagonist. Furthermore, pretreatment with strychnine, a glycine receptor antagonist, blocked the antinociception induced by nicotine, RJR-2403, and choline. On the other hand, the GABAA antagonist bicuculline did not reverse the antiallodynic effect of nicotine. Together, these results indicate that the alpha4beta2 and alpha7 nAChR system, by enhancing the activities of glycinergic neurons at the spinal level, exerts a suppressive effect on the nociceptive transduction in neuropathic pain.

Publisher Summary This chapter discusses novel glycine antagonists as potent neuroprotective agents. Stroke is an abrupt onset of neurological conditions caused by an insufficient cerebral circulation (ischaemic or emorragic). When blood flow is reduced, neuronal cells are deprived of the necessary oxygen supply leading to rapid brain damaged (necrosis). In ischaemic conditions, the reduction of the oxygen–energy supply to the cells causes a significant increase of glutamate within the synaptic cleft. Screening cascade includes (1) binding assay to evaluate the affinity for the glycine site and selectivity for glutamate receptors, (2) in vitro functional antagonism studies to evaluate potency and activity, (3) in vivo anticonvulsant activity in mice, (4) in vivo models of stroke in rats (MCAo). Functional antagonism at the glycine binding site is demonstrated by the ability of new chemical entities (NCE) to antagonize the glycine-induced enhancement of the binding of the channel blocking agent [ 3 H]TCP in a glycine-sensitive extensively washed rat cortical preparation. The assessment of the neuroprotective activity in stroke model, both pre and post-ischemia, is carried out using the permanent occlusion of the middle cerebral artery (MCA) in rats.

Publisher Summary This chapter discusses the role of Ifenprodil and Eliprodil as neuroprotective N-methyl- D -aspartate (NMDA) receptor antagonists and calcium channel blockers. The polyamines and ifenprodil or eliprodil interact with their own particular binding sites and allosterically modify the actions of agonists and antagonists at the glutamate and glycine recognition sites. The polyamine-sensitive ifenprodil site is allosterically modified by figands acting at the glycine and glutamate sites of the NMDA receptor. Ifenprodil and polyamines also have opposing effects on the binding of glycine site antagonists. The modulatory effects of ifenprodil at the glycine site appear to be present at NR1 and NR1/NR2B receptor transfects, where the inhibitory effects of ifenprodil are reduced by glycine, and can also be observed at native NMDA receptors. The various glycine–polyamine interactions also predict that the inhibitory effects of glycine antagonists and ifenprodil should synergize, as demonstrated by in vivo dialysis studies. It is found that Ifenprodil and eliprodil block the depolarizing effects or the increased entry of calcium induced by NMDA in cell culture and glutamate or NMDA-induced neurotoxicity.