Design, Synthesis, and Preliminary Biological Evaluation of New Isoform-Selective f-Current Blockers

Melchiorre, Michele; Lungo, Martina Del; Guandalini, Luca; Martini, Elisabetta; Dei, Silvia; Manetti, Dina; Scapecchi, Serena; Teodori, Elisabetta; Sartiani, Laura; Mugelli, Alessandro; Cerbai, Elisabetta; Romanelli, Maria Novella

doi:10.1021/jm1006758

Cited by 35 publications

(37 citation statements)

References 33 publications

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“…MEL57A is an IVA derivative recently developed by Romanelli and collaborators, with EC50 ¼ 0.32 ± 0.06 mM for HCN1 and 75.26 ± 14.38 mM for HCN4 in transfected HEK293 cells (Melchiorre et al, 2010;Del Lungo et al, 2012). We tested the efficacy of the compound on Ih current in OXA neurons, in which the HCN1 component is predominant.…”

Section: Selective Hcn1 Block Is Sufficient To Revert Oxa-induced Hypmentioning

confidence: 99%

“…New HCN channels-targeted analgesic compounds should feature sufficient selectivity for HCN1 or HCN2 over HCN4 channels expressed in pace-making cells of sinus atrial node, which play a major role during the diastolic depolarization phase of the heart rhythm. To this aim, we tested the HCN1-selective blocker MEL57A, recently developed by Romanelli and collaborators (Del Lungo et al, 2012;Melchiorre et al, 2010). After confirming the capability of MEL57A to reduce the HCN channels conductance in small DRG neurons, we tested it in vivo in increasing doses to study its potential anti-hyperalgesic effect.…”

Section: Selective Block Of Hcn1 Reduces Neuropathy Without Cardiac Smentioning

confidence: 99%

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Selective HCN1 block as a strategy to control oxaliplatin-induced neuropathy

et al. 2018

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a b s t r a c tChemotherapy-Induced Peripheral Neuropathy (CIPN) is the most frequent adverse effect of pharmacological cancer treatments. The occurrence of neuropathy prevents the administration of fully-effective drug regimen, affects negatively the quality of life of patients, and may lead to therapy discontinuation. CIPN is currently treated with anticonvulsants, antidepressants, opioids and non-opioid analgesics, all of which are flawed by insufficient anti-hyperalgesic efficacy or addictive potential. Understandably, developing new drugs targeting CIPN-specific pathogenic mechanisms would dramatically improve efficacy and tolerability of anti-neuropathic therapies. Neuropathies are associated to aberrant excitability of DRG neurons due to the alteration in the expression or function of a variety of ion channels. In this regard, Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels are overexpressed in inflammatory and neuropathic pain states, and HCN blockers have been shown to reduce neuronal excitability and to ameliorate painful states in animal models. However, HCN channels are critical in cardiac action potential, and HCN blockers used so far in pre-clinical models do not discriminate between cardiac and non-cardiac HCN isoforms. In this work, we show an HCN current gain of function in DRG neurons from oxaliplatin-treated rats. Biochemically, we observed a downregulation of HCN2 expression and an upregulation of the HCN regulatory beta-subunit MirP1. Finally, we report the efficacy of the selective HCN1 inhibitor MEL57A in reducing hyperalgesia and allodynia in oxaliplatin-treated rats without cardiac effects. In conclusion, this study strengthens the evidence for a disease-specific role of HCN1 in CIPN, and proposes HCN1-selective inhibitors as new-generation pain medications with the desired efficacy and safety profile.

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Section: Selective Hcn1 Block Is Sufficient To Revert Oxa-induced Hypmentioning

confidence: 99%

Section: Selective Block Of Hcn1 Reduces Neuropathy Without Cardiac Smentioning

confidence: 99%

Selective HCN1 block as a strategy to control oxaliplatin-induced neuropathy

et al. 2018

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“…However, the current I h -specific compounds work in the lM, but not nanomolar, range (Postea and Biel, 2011), and most of them including ZD7288 (Shin et al, 2001;Cheng et al, 2007) require intra-cellular access to exert their effects, but extra-cellular binding is preferable (Postea and Biel, 2011). Attempts are currently on-going to produce HCN-subunit-selective antagonists (Melchiorre et al, 2010).…”

Section: Peripheral Blockade Of Hcn Channels Attenuates Spontaneous Pmentioning

confidence: 99%

Increased expression of HCN2 channel protein in L4 dorsal root ganglion neurons following axotomy of L5- and inflammation of L4-spinal nerves in rats

Smith¹,

Otaibi²,

Sathish³

et al. 2015

Neuroscience

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“…Ivabradine is a reasonably selective I f current blocker [299], however, additional ion channel blocking effects of ivabradine have been identified that could contribute to its antiarrhythmic activity [300]. Recently, some important steps have been made in the development of new I f blockers showing relative isoform selectivity [301], and EC18 was identified as a selective HCN4 blocker that slowed the slope of diastolic depolarization in canine Purkinje fibers [302]. Further studies are needed, however, to determine the effects of isoform selective I f blockers on enhanced triggered activity in experimental HF.…”

Section: F Blockersmentioning

confidence: 99%

Future Perspectives in the Pharmacological Treatment of Atrial Fibrillation and Ventricular Arrhythmias in Heart Failure

Baczkó

Leprán

Kiss

et al. 2014

CPD

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Heart failure (HF) is a clinical syndrome characterized by significant impairment of cardiac ventricular function. Atrial fibrillation (AF) is the most commonly observed sustained arrhythmia in clinical practice. Both HF and AF are associated with increased morbidity and mortality and their prevalence increases with age. Approximately 50% of patients with moderate HF die due to ventricular fibrillation that leads to sudden cardiac death. Patients with AF exhibit increased mortality due to HF and stroke. HF and AF often co-exist, and the development of the other condition further deteriorates prognosis. Both chronic HF and AF lead to structural and electrophysiological changes in the heart called remodeling, modifying therapeutic targets including those for antiarrhythmic intervention. Current pharmacological treatment of arrhythmias has major limitations due to low efficacy and serious adverse effects. In this review, the main aspects of electrical remodeling in HF and AF are discussed along with possible novel targets identified for future pharmacological antiarrhythmic therapy.Keywords: Heart failure, atrial fibrillation, cardiac arrhythmias, electrical remodeling, potassium channel expression, multi-channel blocking drugs. I. OVERVIEW AND CURRENT STATUS Epidemiology of Heart Failure, Atrial Fibrillation and their CombinationHeart failure (HF) is a clinical syndrome resulting from a wide range of cardiovascular disorders, featuring significant impairment of cardiac function that leads to reduced ventricular filling or ejection of blood. HF markedly reduces health-related quality of life [1], causes significant morbidity and high mortality and represents an enormous economic burden for the health care system [2]. The incidence of HF is increasing with age, with 20 per 1000 persons 65-69 years old and more than 80 per 1000 persons older than 85 [3] and its prevalence is increasing in a continuously aging population [2]. In spite of the significant advances in the treatment of HF, mortality rates remain poor at approximately 50% of patients dying within 5 years of diagnosis [4]. Serious ventricular arrhythmias are common in HF [5] and approximately 50% of HF patients die due to ventricular fibrillation leading to sudden cardiac death (SCD), the rate of which is several times higher in HF patients compared to the general population [6]. In addition to severe ventricular arrhythmias, atrial arrhythmias often develop in heart failure. Bradycardia can develop due to sinoatrial function impairment [7] that can exacerbate cardiac dysfunction [8], can lead to syncope and haemodynamic collapse and can be resolved by application of implantable devices [9].Atrial fibrillation (AF) is the most common sustained arrhythmia and it is associated with significant morbidity and mortality, especially due to the increased risk of heart failure and stroke [10][11][12]. The prevalence of AF increases with age, with 0.5% of patients affected in the 50 year old range, ~10% over the age of 80 [13] and the prediction is that it...

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Design, Synthesis, and Preliminary Biological Evaluation of New Isoform-Selective f-Current Blockers

Cited by 35 publications

References 33 publications

Selective HCN1 block as a strategy to control oxaliplatin-induced neuropathy

Selective HCN1 block as a strategy to control oxaliplatin-induced neuropathy

Increased expression of HCN2 channel protein in L4 dorsal root ganglion neurons following axotomy of L5- and inflammation of L4-spinal nerves in rats

Future Perspectives in the Pharmacological Treatment of Atrial Fibrillation and Ventricular Arrhythmias in Heart Failure

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