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Drug therapy
Published in Jeremy Playfer, John Hindle, Andrew Lees, Parkinson's Disease in the Older Patient, 2018
Anti-glutamate antagonists and NMDA receptor antagonists have efficacy in controlling dyskinetic movements. Drugs such as such riluzole and remacemide have so far produced disappointing results in clinical trials.88,89 Idazoxan and alpha-adrenergic antagonists have been studied for their anti-dyskinetic activity and are now under clinical trials.90 Drugs that may modify free-radical generations, such as spin trap agents or antioxidants, continue to be widely researched in animal models. Drugs targeting opioid and cannabinoid receptors are at an early stage of development.91
Adrenoceptor Antagonists
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
Whether idazoxan or other α2-adrenoceptor antagonists have potential clinical applications remains to be seen. A likely use was in the treatment of maturity-onset type II diabetes. Since the α2-agonist, clonidine, inhibits insulin secretion via stimulation of postjunctional α2-adrenoceptors of the pancreatic β cells, selective antagonists might be expected to increase insulin secretion, providing there was sufficient tonic inhibition of insulin release from endogenous catecholamines (Table 3.4). The non-selective antagonist, phentolamine, increases basal and glucose-stimulated insulin levels in man (Robertson & Porte 1973). Idazoxan, however, failed to affect insulin levels in man in response to glucose, but facilitated the response to adrenaline (Struthers et al. 1985). It is also possible that concommitant blockade of prejunctional α2-adrenoceptors on the sympathetic nerve will enhance noradrenaline release; if the postjunctional α2-adrenoceptors are blocked the noradrenaline could activate β-adrenoceptors which promote secretion of insulin (Duval et al. 1991).
Alpha adrenergic receptors have role in the inhibitory effect of electrical low frequency stimulation on epileptiform activity in rats
Published in International Journal of Neuroscience, 2023
Mahmoud Rezaei, Nooshin Ahmadirad, Zahra Ghasemi, Amir Shojaei, Mohammad Reza Raoufy, Victoria Barkley, Yaghoub Fathollahi, Javad Mirnajafi-Zadeh
We previously suggested that Gi-coupled receptors may play role in LFS’ anticonvulsive action [27]. Therefore, α2 adrenergic receptors mediating role in LFS’ inhibitory action can be explained through Gi signaling. Modulation of K+ channel conductance involves in both α1 and α2 adrenoceptor-mediated changes in excitability. Activation of α2 receptors has been shown to hyperpolarize neurons through Gi proteins [28]. More specifically, an increase in K+ conductance (which would be hyperpolarizing) appears to underlie the inhibitory effects mediated by α2 receptors. However, in high K+ solution, potassium is prevented to leave the cell due to its high concentration outside the cell. Experiments revealed that, the alpha2-antagonist idazoxan increased the firing the rate and burst firing of VTA-dopamine neurons, as described previously [29].
Can therapeutic strategies prevent and manage dyskinesia in Parkinson’s disease? An update
Published in Expert Opinion on Drug Safety, 2019
Valentina Leta, Peter Jenner, K. Ray Chaudhuri, Angelo Antonini
Noradrenergic dysfunction has also been observed in LID. Antagonists of α and β adrenergic receptors reduced LID in animal models probably by decreasing the hyperactivity of the direct striato-pallidal pathway [100]. Despite the encouraging results of a small, single-dose pilot study [101], the selective α 2A antagonists, idazoxan, did not provide robust evidence of efficacy in treating dyskinesia in PD patients in a clinical trial [102]. Also, fipamezole, which is a selective α 2A/2C adrenergic receptor antagonist, failed to show its anti-dyskinetic properties in an international phase II clinical trial; however, secondary analyses of outcomes revealed that findings where discordant between international cohorts and fipamezole was partly effective in reducing LID in the US cohort of this trial [103].
The latest automated docking technologies for novel drug discovery
Published in Expert Opinion on Drug Discovery, 2021
It is common in literature the use of reverse docking to detect adverse drug reactions and drug toxicities. For instance, Eric et al [55] performed a reverse docking protocol to investigate the cytotoxic activity of a set of 16 previously synthesized arylaminopyridine and arylaminoquinoline derivatives. Among the included potential targets explored in their investigation, they proposed that protein kinases (PKs) and topoisomerase I are responsible of the cytotoxic effect of aminopyridines. In other work, Fan et al [56] used network pharmacology and reverse docking to investigate the adverse effects of the drug torcetrapib related to increase of mortality and cardiac events. Authors docked torcetrapib into a set of protein targets based on enriched signaling pathways and found four potential off-targets: platelet-derived growth factor receptor (PDGFR), hepatocyte growth factor receptor (HGFR), IL-2 Receptor, and ErbB1 tyrosine kinase. In other work, Ma et al [57] applied a reverse docking protocol to predict the toxicity-related target proteins for melamine and cyanuric acid (a melamine metabolite). Authors identified four target proteins related to the molecular basis of the nephrotoxicity induced by melamine. In a more recent work, Djikic et al [58] performed a reverse docking protocol on 107 class A GPCRs, using 63 imidazoline ligands and their decoys, to investigate possible off-target effects of these ligands. Authors verified their in silico results by evaluating the antagonistic activity on α2-adrenoceptors of ligands with high and low scores. They found potential off-target GPCRs for efaroxan and idazoxan and proposed mechanisms to understand side effects of these drugs.