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Calcium Channel Antagonists (calcium + channel_antagonist)
Selected AbstractsSynthesis of 4-(1-Phenylmethyl-5-imidazolyl)-1,4-dihydropyridines as Calcium Channel Antagonists.CHEMINFORM, Issue 13 2003F. Hadizadeh Abstract For Abstract see ChemInform Abstract in Full Text. [source] Hantzsch 1,4-dihydropyridines containing a nitrooxyalkyl ester moiety to study calcium channel antagonist structure,activity relationships and nitric oxide releaseDRUG DEVELOPMENT RESEARCH, Issue 4 2000Jeffrey-Tri Nguyen Abstract A group of 3-nitrooxyalkyl 5-alkyl 1,4-dihydro-2,6-dimethyl-4-(pyridyl)-3,5-pyridinedicarboxylates were prepared using a modified Hantzsch reaction that involved the condensation of a nitrooxyalkyl acetoacetate with an alkyl 3-aminocrotonate and a pyridinecarboxaldehyde. 1H NMR nuclear Overhauser enhancement (nOe) studies for 3-(3-nitrooxypropyl) 5-isopropyl 1,4-dihydro-2,6-dimethyl-4-(2-pyridyl)-3,5-pyridinedicarboxylate (17) indicates a predominant rotamer exists in solution where the pyridyl nitrogen atom is orientated above the 1,4-DHP ring system, and the pyridyl nitrogen atom is antiperiplanar to the 1,4-DHP ring H-4 proton. Variable temperature 1H NMR studies (,30 to +60°C) showed the 1,4-DHP NH proton in 17 is H-bonded in CHCl3 solution. This interaction is believed to be due to intermolecular H-bonding between the pyridyl nitrogen free electron pair and the 1,4-DHP NH proton. In vitro calcium channel antagonist (CCA) activities were determined using a muscarinic-receptor-mediated Ca+2 -dependent contraction of guinea pig ileal longitudinal smooth muscle assay. This class of compounds exhibited lower CCA activity (IC50 = 5.3 × 10,6 to 3.5 × 10,8 M range) than the reference drug nifedipine (IC50 = 1.4 × 10,8 M). For compounds having C-3 ,CH2CH2ONO2 and C-4 pyridyl substituents, the C-5 alkyl was a determinant of CCA (i -Pr > the approximately equipotent i -Bu, t -Bu, and Et analogs). The point of attachment of the isomeric C-4 pyridyl substituent was a determinant of CCA when C-3 ,CH2CH2ONO2 and C-5 i -Pr substituents were present providing the potency profile 2-pyridyl , 3-pyridyl > 4-pyridyl. CCA with respect to the C-3 nitrooxyalkyl substituent was inversely dependent on the length of the alkyl spacer. The percent nitric oxide (·NO) released in vitro by this group of compounds (range of 0.03,0.43%/ONO2 group), quantified as nitrite by reaction with the Griess reagent, was lower than that for the reference drug glycerol trinitrate (3.81%/ONO2 group). Nitric oxide release studies showed that the %·NO released was dependent on the number of ONO2 groups/molecule. A QSAR study for this group of compounds showed a correlation between the specific polarizability descriptor (SpPol) and %·NO release. Drug Dev. Res. 51:233,243, 2000. © 2001 Wiley-Liss, Inc. [source] Calcium Channel Antagonism Reduces Exercise-Induced Ventricular Arrhythmias in Catecholaminergic Polymorphic Ventricular Tachycardia Patients with RyR2 MutationsJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 2 2005HEIKKI SWAN M.D. Introduction: Recently, gain-of-function mutations of cardiac ryanodine receptor RyR2 gene have been identified as a cause of familial or catecholaminergic polymorphic ventricular tachycardia. We examined the influence of the calcium channel blockers, verapamil and magnesium, on exercise-induced ventricular arrhythmias in patients with RyR2 mutations. Methods and Results: Six molecularly defined catecholaminergic polymorphic ventricular tachycardia patients, all carrying a RyR2 mutation and on ,-adrenergic blocker therapy, underwent exercise stress test four times: at baseline, after verapamil and magnesium sulphate infusions, and finally, without interventions. The number of isolated and successive premature ventricular complexes during exercise ranged from 40 to 374 beats (mean 165 beats) at baseline, and was reduced during verapamil by 76 ± 17% (P < 0.05). Premature ventricular complexes appeared later and at higher heart rate during verapamil than at baseline (119 ± 21 vs. 127 ± 27 min,1, P < 0.05). Magnesium did not inhibit the arrhythmias. Results in the fourth exercise stress test without interventions were similar to those in the first baseline study. Conclusions: This study provides the first in vivo demonstration that a calcium channel antagonist, verapamil, can suppress premature ventricular complexes and nonsustained ventricular salvoes in catecholaminergic polymorphic ventricular tachycardia caused by RyR2 mutations. Modifying the abnormal calcium handling by calcium antagonists might have therapeutic value. [source] Synthesis of alkyl 6-methyl-4-(2-pyridyl)-1,2,3,4-tetrahydro-2H -pyrimidine-2-one-5-carboxylates for evaluation as calcium channel antagonistsJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 3 2007Kuljeet Kaur The Bigenelli acid catalyzed condensation of 2-pyridylcarboxaldehyde (1), urea (2) and an alkyl acetoacetate (3) afforded the respective alkyl (Me, Et, i -Pr, i -Bu, t -Bu) 6-methyl-4-(2-pyridyl)-1,2,3,4-tetrahydro-2H -pyrimidine-2-one-5-carboxylates (4a-e). The most potent calcium channel antagonist ethyl 6-methyl-4-(2-pyridyl)-1,2,3,4-tetrahydro-2H -pyrimidine-2-one-5-carboxylate (4b, IC50 = 1.67 × 10,5 M) wasa much weaker calcium channel antagonist than the reference drug nifedipine (Adalat®, IC50 = 1.40 × 10,8 M) on guinea pig ileal longitudinal smooth muscle (GPILSM). The alkyl 6-methyl-4-(2-pyridyl)-1,2,3,4-tetrahydro-2H -pyrimidine-2-one-5-carboxylates did not show any inotropic effect on heart since no increase, or decrease, in the contractile force of guinea pig left atrium was observed. These structure activity studies show that the alkyl 6-methyl-4-(2-pyridyl)-1,2,3,4-tetrahydro-2H -pyrimidine-2-one-5-carboxylates (4a-e) are partial bioisosteres of nifedipine with respect to calcium channel antagonist activity on guinea pig ileal longitudinal smooth muscle (GPILSM). [source] Characterization of a novel NCAM ligand with a stimulatory effect on neurite outgrowth identified by screening a combinatorial peptide libraryEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2002Lars C. B. Rønn Abstract The neural cell adhesion molecule, NCAM, plays a key role in neural development and plasticity mediating cell adhesion and signal transduction. By screening a combinatorial library of synthetic peptides with NCAM purified from postnatal day 10 rat brains, we identified a nonapeptide, termed NCAM binding peptide 10 (NBP10) and showed by nuclear magnetic resonance analysis that it bound the NCAM IgI module of NCAM. NBP10 modulated cell aggregation as well as neurite outgrowth induced specifically by homophilic NCAM binding. Moreover, both monomeric and multimeric forms of NBP10 stimulated neurite outgrowth from primary hippocampal neurons. The neurite outgrowth response to NBP10 was inhibited by a number of compounds previously shown to inhibit neurite outgrowth induced by homophilic NCAM binding, including voltage-dependent calcium channel antagonists, suggesting that NBP10 induced neurite outgrowth by activating a signal transduction pathway similar to that activated by NCAM itself. Moreover, an inhibitor of intracellular calcium mobilization, TMB-8, prevented NBP10-induced neurite outgrowth suggesting that NCAM-dependent neurite outgrowth also requires mobilization of calcium from intracellular calcium stores in addition to calcium influx from extracellular sources. By single-cell calcium imaging we further demonstrated that NBP10 was capable of inducing an increase in intracellular calcium in PC12E2 cells. Thus, the NBP10 peptide is a new tool for the study of molecular mechanisms underlying NCAM-dependent signal transduction and neurite outgrowth, and could prove to be a useful modulator of regenerative processes in the peripheral and central nervous system. [source] Modulation of glycine responses by dihydropyridines and verapamil in rat spinal neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2001Dominique Chesnoy-Marchais Abstract Although glycine receptors (GlyRs) are responsible for the main spinal inhibitory responses in adult vertebrates, in the embryo they have been reported to mediate depolarizing responses, which can sometimes activate dihydropyridine-sensitive l -type calcium channels. However, these channels are not the only targets of dihydropyridines (DHPs), and we questioned whether GlyRs might be directly modulated by DHPs. By whole-cell recording of cultured spinal neurons, we investigated modulation of glycine responses by the calcium channel antagonists, nifedipine, nitrendipine, nicardipine and (R)-Bay K 8644, and by the calcium channel, agonist (S)-Bay K 8644. At concentrations between 1 and 10 µm, all these DHPs could block glycine responses, even in the absence of extracellular Ca2+. The block was stronger at higher glycine concentrations, and increased with time during each glycine application. Nicardipine blocked GABAA responses from the same neurons in a similar manner. In addition to their blocking effects, nitrendipine and nicardipine potentiated the peak responses to low glycine concentrations. Both effects of extracellular nitrendipine on glycine responses persisted when the drug was present in the intracellular solution. Thus, these modulations are related neither to calcium channel modulation nor to possible intracellular effects of DHPs. Another type of calcium antagonist, verapamil (10,50 µm), also blocked glycine responses. Our results suggest that some of the effects of calcium antagonists, including the neuroprotective and anticonvulsant effects of DHPs, might result partly from their interactions with ligand-gated chloride channels. [source] Synthesis of alkyl 6-methyl-4-(2-pyridyl)-1,2,3,4-tetrahydro-2H -pyrimidine-2-one-5-carboxylates for evaluation as calcium channel antagonistsJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 3 2007Kuljeet Kaur The Bigenelli acid catalyzed condensation of 2-pyridylcarboxaldehyde (1), urea (2) and an alkyl acetoacetate (3) afforded the respective alkyl (Me, Et, i -Pr, i -Bu, t -Bu) 6-methyl-4-(2-pyridyl)-1,2,3,4-tetrahydro-2H -pyrimidine-2-one-5-carboxylates (4a-e). The most potent calcium channel antagonist ethyl 6-methyl-4-(2-pyridyl)-1,2,3,4-tetrahydro-2H -pyrimidine-2-one-5-carboxylate (4b, IC50 = 1.67 × 10,5 M) wasa much weaker calcium channel antagonist than the reference drug nifedipine (Adalat®, IC50 = 1.40 × 10,8 M) on guinea pig ileal longitudinal smooth muscle (GPILSM). The alkyl 6-methyl-4-(2-pyridyl)-1,2,3,4-tetrahydro-2H -pyrimidine-2-one-5-carboxylates did not show any inotropic effect on heart since no increase, or decrease, in the contractile force of guinea pig left atrium was observed. These structure activity studies show that the alkyl 6-methyl-4-(2-pyridyl)-1,2,3,4-tetrahydro-2H -pyrimidine-2-one-5-carboxylates (4a-e) are partial bioisosteres of nifedipine with respect to calcium channel antagonist activity on guinea pig ileal longitudinal smooth muscle (GPILSM). [source] The pharmacology of the internal anal sphincter and new treatments of ano-rectal disordersALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 7 2001T. A. Cook Surgical options for faecal incontinence in the presence of intact sphincters are limited. Furthermore, in patients with fissures, lateral sphincterotomy reduces anal sphincter hypertonia but there has been concern about complications. A greater understanding of the basic pharmacology of the internal anal sphincter has led to the development of novel treatments for both these disorders. A Medline review was undertaken for internal anal sphincter pharmacology, anal fissures and faecal incontinence. This review is based on these articles and those found by further cross-referencing. ,Nitric oxide released from non-adrenergic non-cholinergic nerves is the main inhibitory agent in the internal anal sphincter. Relaxations are also mediated through ,-adrenoceptors and muscarinic receptors. Stimulation of ,-receptors results in contraction. Calcium and its entry through L -type calcium channels is important for the maintenance of tone. Nitric oxide donors produce reductions in resting anal tone and heal fissures but are associated with side-effects. Muscarinic agents and calcium channel antagonists show promise as low side-effect alternatives. Botulinum toxin appears more efficacious than other agents in healing fissures. To date, ,-receptor agonists have been disappointing at improving incontinence. Further understanding of the pharmacology of the internal anal sphincter may permit the development of new agents to selectively target the tissue with greater efficacy and fewer side-effects. [source] Relaxant responses to calcium channel antagonists and potassium channel opener in human saphenous veinAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1 2006C. Ford Summary 1 As shown in a parallel study the magnitude of depolarization induced in human saphenous vein by raising external potassium ([K+]e) falls markedly below the theoretical values predicted by the Goldman,Hodgkin,Katz equations. This anomaly prompted us to re-examine the relaxant actions of L-type (nifedipine) and T-type (mibefradil) Ca2+ channel antagonists, and relaxant and electrophysiological effects of the K+ channel opener, pinacidil, on saphenous veins contracted by the elevation of [K+]e. 2 Nifedipine produced concentration,dependent relaxations in tissues contracted at various high [K+]e. In tissues contracted with 20 mm [K+]e, the pIC50 for nifedipine was significantly (8.20 ± 0.05; n = 6; mean ± SEM; P < 0.05) greater than in tissues contracted with ,40 mm [K+]e. 3 Tissues contracted with 20 mm [K+]e also relaxed in response to mibefradil (pIC50 = 6.1 ± 0.14) and pinacidil (pIC50 = 6.45 ± 0.08), the latter being almost completely reversed (93.4 ± 9.9%) by addition of glibenclamide (10 ,m). 4 The resting Em of smooth muscle cells of saphenous vein was ,77.0 ± 0.7 mV (n = 52), and 20 mm [K+]e produced a modest but significant depolarization to ,73.0 ± 0.7 mV (n = 52). Incubation with pinacidil plus 20 mm [K+]e resulted in a significant hyperpolarization of the Em to ,82 ± 0.6 mV (n = 52). 5 N, -nitro- l -arginine methyl ester did not impede the relaxant responses of nifedipine, mibefradil or pinacidil. 6 In conclusion, the relaxant effects of nifedipine and pinacidil (i) occurred at an Em distinctly below the presumed threshold for the opening of the classic (CaV1.3,1) L-type Ca2+ channels, and (ii) did not depend on generation of nitric oxide. [source] | |||||||||||||