Class Of Calcium Channel Antagonists Research Articles

Nanosuspension – Preparation,In VitroandEx VivoEvaluations of Felodipine Hydrochloride

Felodipine is a member of the dihydropyridine class of calcium channel antagonists (calcium channel blockers) and is insoluble in water. The main objective of this study to design a nanosuspension formulation using hydroxyl propyl methyl cellulose and hydroxyl propyl cellulose. Drug polymers interactions were studied by Differential Scanning Colorimetry. Precipitation method has been used to prepare nanosuspension particles of poorly soluble drug. The prepared nanosuspensions were characterized for droplet size, pH, viscosity, refractive index, surface morphology by Transmission Electron Microscopy (TEM), drug entrapment efficiency, zeta potential, in vitro skin permeation, drug release kinetic, histopathological and stability studies. The droplet size was in the ranges of 61.2±0.58 (F3) to 91.4±0.79 nm (F5). Most nanosuspension possesses a very low viscosity and, therefore, their application may be convenient. The pH value of all the felodipine nanosuspension formulation was in the skin pH range, which was nearer to neutral pH range, demonstrating that all the felodipine nanosuspension will be non toxic, non irritating and non allergic. The felodipine nanosuspension formulation F3 containing 0.75% HPMC K4M, could be concluded as the best optimized formulation for safe management of hypertension. The optimized felodipine nanosuspension formulation F3 was found to be stable for both short and long term period in various storage conditions. Skin irritation test revels that no erythema was observed on visual inspection after application of felodipine nanosuspension formulations on rat skin. Thus, the developed formulation is non-sensitizing and safe for use.

An in vivo antilymphatic screen in zebrafish identifies novel inhibitors of mammalian lymphangiogenesis and lymphatic-mediated metastasis.

The growth of new lymphatic vessels (lymphangiogenesis) in tumors is an integral step in the metastatic spread of tumor cells, first to the sentinel lymph nodes that surround the tumor and then elsewhere in the body. Currently, no selective agents designed to prevent lymphatic vessel growth have been approved for clinical use, and there is an important potential clinical niche for antilymphangiogenic agents. Using a zebrafish phenotype-based chemical screen, we have identified drug compounds, previously approved for human use, that have antilymphatic activity. These include kaempferol, a natural product found in plants; leflunomide, an inhibitor of pyrimidine biosynthesis; and cinnarizine and flunarizine, members of the type IV class of calcium channel antagonists. Antilymphatic activity was confirmed in a murine in vivo lymphangiogenesis Matrigel plug assay, in which kaempferol, leflunomide, and flunarizine prevented lymphatic growth. We show that kaempferol is a novel inhibitor of VEGFR2/3 kinase activity and is able to reduce the density of tumor-associated lymphatic vessels as well as the incidence of lymph node metastases in a metastatic breast cancer xenograft model. However, in this model, kaempferol administration was also associated with tumor deposits in the pancreas and diaphragm, and flunarizine was found to be tumorigenic. Although this screen revealed that zebrafish is a viable platform for the identification and development of mammalian antilymphatic compounds, it also highlights the need for focused secondary screens to ensure appropriate efficacy of hits in a tumor context.

Dihydropyridines and Multidrug Resistance: Previous Attempts, Present State, and Future Trends

Multidrug resistance is defined as the resistance of a tumor cell to the cytotoxic action of divergent drugs used in chemotherapy. Dihydropyridines are a class of calcium channel antagonists that were discovered to have a multidrug resistance reversing effect and prompted investigations resulting in the synthesis of hundreds of new derivatives. Most of the investigators tried to achieve two goals: a decrease in Ca²(+) channel-blocking activity and an increase in the multidrug resistance reversing effect. Most of the synthesized compounds failed in the later stages of studies especially in clinical trials because of pharmacokinetic or pharmacodynamic limitations. Therefore, it will be necessary to include new methods, such as combinatorial synthesis, and, more importantly, to apply computational methods based on global structure-activity relationship models that consider all problems. Moreover, some compounds should be synthesized that are effective on several multidrug resistance targets.

Synthesis, QSAR and Calcium Channel Modulator Activity of New Hexahydroquinoline Derivatives Containing Nitroimidazole

The discovery that 1,4-dihydropyridine class of calcium channel antagonists inhibit Ca2+ influx represented a major therapeutic advance in the treatment of cardiovascular disease. In contrast to the effects of known calcium channel blockers of the Nifedipine-type, the so-called calcium channel agonists, such as Bay K8644 and CGP 28392, increase calcium influx by binding at the same receptor regions. Our goal was to discover a dual cardioselective Ca2+-channel agonist/vascular selective smooth muscle Ca2+ channel antagonist third-generation 1,4-dihydropyridine drug which would have a suitable therapeutic profile for treating congestive heart failure (CHF) patients. A series of unsymmetrical alkyl, cycloalkyl and aryl ester analogues of 2-methyl-4-(1-methyl)-5-nitro-2-imidazolyl-5-oxo-1,4,5,6,7, 8-hexahydroquinolin-3-arboxylate were synthesized using modified Hantzsch reaction. All compounds show calcium antagonist activity on guinea-pig ileum longitudinal smooth muscle and some of them show agonist effect activity on guinea-pig auricle. Effect of structural parameters on the Ca2+ channel agonist/antagonist was evaluated by quantitative structure-activity relationship analysis. These compounds could be considered as a synthon for developing a suitable drug for treating CHF patients.

Exploration of the Ca2+ Interaction Modes of the Nifedipine Calcium Channel Antagonist

A comprehensive study is carried out using quantum chemical computation and molecular dynamics (MD) simulations to gain insight into the interaction between Ca(2+) ions and the most important class of calcium channel antagonists--nifedipine. First, the chelating structures and energetic characters of nifedipine-Ca(2+) in the gas phase are explored, and 25 isomers are found. The most favorable chelating mode is a tridentate one, that is, Ca(2+) binds to two carbonyl O atoms and one nitryl O atom, where Ca(2+) is above the plane of the three O atoms to form a pyramidal structure. Accurate geometric structures, relative stabilities, vertical and adiabatic binding energies, and charge distributions are discussed. The differences in the geometries and energies among these isomers are analyzed from the contributions of chelating sites, electrostatics and polarizations, steric repulsions, and charge distributions. The interconversions among isomers with similar geometries and energies are also investigated because of the importance of the geometric transformation in the biological system. Furthermore, certain numbers of water molecules are added to the nifedipine-Ca(2+) system to probe the effect of water. A detailed study is performed on the hydrated geometries on the basis of the most stable isomer 1. Stepwise hydration can weaken the nifedipine-Ca(2+) interaction, and the chelating sites of nifedipine are gradually replaced by the added water molecules. Hexacoordination is found to be the most favorable geometry no matter how many water molecules were added, which can be verified by the MD simulations. The transfer of water molecules from the inner shell to the outer shell is also supported by MD simulations of the hexahydrated complexes.

Design and synthesis of alkyl 7,7-dihalo-3-methyl-5-(nitrophenyl)-2-azabicyclo[4.1.0]hept-3-ene-4-carboxylates with calcium channel antagonist activity

A group of alkyl 7,7-dihalo-3-methyl-5-(2- or 3-nitrophenyl)-2-azabicyclo[4.1.0]hept-3-ene-4-carboxylates were prepared by reaction of dihalocarbenes (:CX 2, X = Br, Cl) with alkyl 2-methyl-4-(2- or 3-nitrophenyl)-1,4-dihydropyridine-3-carboxylates. In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle assay. The title compounds exhibited weaker CC antagonist activity (10 −5 to 10 −7 M range) than the reference drug nifedipine (1.4 × 10 −8 M). Structure–activity relationships showed that the position ( ortho or meta) of the nitro-substituent on the C-5 phenyl ring, the size (van der Waal’s radius for Br and Cl are 1.95 and 1.80 Å, respectively) and/or electronegativity (Cl > Br) of the C-7 geminal halogen atoms do not appear to have a significant effect on CC antagonist activity. In contrast, the effect of the alkyl ester substituent was more pronounced where compounds having a Me or Et alkyl ester group showed superior potency (IC 50 in the 10 −7 M range) relative to the reference drug nifedipine (IC 50 = 1.40 × 10 −8 M). Replacement of a 2-methyl-3-methoxycarbonylvinyl moiety present in nifedipine by a bioisosteric geminal-dihalocyclopropyl moiety provided a novel class of calcium channel antagonists that do not exhibit any inotropic effect on guinea pig atria.

Vascular Effects of Calcium Channel Antagonists: New Evidence

Calcium channel antagonists have a well-established role in the management of cardiovascular diseases. L-type calcium channels in vascular cells are a key therapeutic target in hypertension and are the preferred molecular target of the initial calcium channel antagonists. However, third-generation dihydropyridine (DHP) calcium channel antagonists, including manidipine, nilvadipine, benidipine and efonidipine, appear to have effects in addition to blockade of the L-type calcium channel. Voltage-gated calcium channels are widely expressed throughout the cardiovascular system. They constitute the main route for calcium entry, essential for the maintenance of contraction. Cardiac and vascular cells predominantly express L-type calcium channels. More recently, T-type channels have been discovered, and there is emerging evidence of their significance in the regulation of arterial resistance. A lack of functional expression of L-type channels in renal efferent arterioles may be consistent with an important role of T-type channels in the regulation of efferent arteriolar tone. Although the exact role of T-type calcium channels in vascular beds remains to be determined, they could be associated with gene-activated cell replication and growth during pathology. The three major classes of calcium channel antagonists are chemically distinct, and exhibit different functional effects depending on their biophysical, conformation-dependent interactions with the L-type calcium channel. The DHPs are more potent vasodilators, and generally have less cardiodepressant activity than representatives of other classes of calcium channel antagonist such as diltiazem (a phenylalkylamine) and verapamil (a benzothiazepine). In contrast to older calcium channel antagonists, the newer DHPs, manidipine, nilvadipine, benidipine and efonidipine, dilate not only afferent but also efferent renal arterioles, a potentially beneficial effect that may improve glomerular hypertension and provide renoprotection. The underlying mechanisms for the heterogenous effects of calcium channel antagonists in the renal microvasculature are unclear. A credible hypothesis suggests a contribution of T-type calcium channels to efferent arteriolar tone, and that manidipine, nilvadipine and efonidipine inhibit both L and T-type channels. However, other mechanisms, including an effect on neuronal P/Q-type calcium channels (recently detected in arterioles), the microheterogeneity of vascular beds, and other types of calcium influx may also play a role. This article presents recent data about the expression and physiological role of calcium channels in arteries and the molecular targets of the calcium channel antagonists, particularly those exhibiting distinct renovascular effects.

Identification of a calcium channel modulator using a high throughput yeast two-hybrid screen.

The interaction of the N-type calcium channel beta3 subunit with the alpha1B subunit alters the activation/inactivation kinetics and the maximal conductance of the channel. The defined protein-protein interaction of the human alpha1B and beta3 subunits provides a target for small-molecule modulation of N-type channel activity. We describe a high throughput screen based on a counterselection yeast two-hybrid assay, which was used to identify small molecules that disrupt alpha1B-beta3 subunit interactions and inhibit N-type calcium channel activity. These small molecules may be a new class of calcium channel antagonists with therapeutic potential.

Mibefradil: a new class of calcium-channel antagonists.

To describe the pharmacology, pharmacokinetics, and clinical efficacy of mibefradil compared with other agents used for hypertension and angina. A MEDLINE search was performed for the period of January 1980 through September 1997 using the key terms mibefradil or Ro 40-5967. All articles written in English were considered for review. All clinical studies involving mibefradil were evaluated. Preclinical data were included if these data were not adequately represented in clinical (human) studies. Mibefradil is the first member of a new class of calcium-channel antagonists (CCAs) that block the T-type calcium channels. A long elimination half-life makes once-daily dosing feasible, and the drug's lack of negative inotropy and reflex tachycardia distinguishes it from other available CCAs. When administered at recommended dosages (50 or 100 mg once daily), mibefradil reduces blood pressure over 24 hours in patients with hypertension, improves exercise capacity, and relieves anginal symptoms in patients with chronic stable angina pectoris. Clinical studies have found that the antihypertensive effects of mibefradil are comparable with those of nifedipine, verapamil, and amlodipine, and more effective than those of diltiazem. These effects result from peripheral vasodilation and a slight reduction in heart rate. Selective vasodilation of the coronary vasculature makes it an effective antianginal agent when used alone or added to beta-blocker therapy. Mibefradil demonstrates no significant effects on cardiac contractility, and no adrenergic stimulation resulting in reflex tachycardia. Therefore, it may have some advantages over currently available CCAs, especially in patients with congestive heart failure, although such advantages are unproven in published clinical trials. Ongoing clinical studies, including the Mortality Assessment in Congestive Heart Failure Trial (MACH-1) currently in progress, are needed to clarify mibefradil's place in cardiovascular therapy.

Prognosis of patients with unstable angina or acute myocardial infarction treated with calcium channel antagonists

The safety of calcium channel antagonists has become a controversial issue among cardiologists. Thus, the role of calcium antagonists in the treatment of myocardial infarction is reviewed, and the differences among the 3 classes of calcium channel antagonists, phenylalkylamines, dihydropyridines, and benzothiazepines, are discussed.

Use of Calcium Channel Antagonists for cardiovascular disease: This CE program reviews the role of calcium channel antagonists in managing certain diseases and compares agents

Until recently, only three calcium channel antagonists--verapamil, diltiazem and nifedipine--were available for managing cardiovascular disorders such as hypertension and ischemic heart disease. In the past few years, however, several dihydropyridine calcium channel antagonists, including nicardipine, isradipine, felodipine, nimodipine, and amlodipine, have been marketed. Others are currently awaiting FDA approval. In addition, bepridil, which belongs to a new class of calcium channel antagonists, has recently been marketed for refractory angina pectoris. Clinical uses of calcium channel antagonists have been expanded since the 1970s to include management of cardiovascular disorders such as supraventricular arrhythmias, CHF secondary to diastolic dysfunction, and myocardial reinfarction in selected patients. Calcium channel antagonists are also being investigated for prevention of atherosclerosis. Calcium channel antagonists are a heterogeneous group of pharmacologic agents. Differences in tissue selectivity are largely responsible for the variations in hemodynamic and electrophysiologic properties of these agents. Thus, their clinical uses and side effect profiles differ. These differences must be taken into consideration in the selection of the most appropriate agent for a specific indication. Potential advantages of some of the newer dihydropyridine calcium channel antagonists include less frequent dosing (amlodipine and isradipine) and little or no negative inotropic effect (nicardipine, felodipine, amlodipine, isradipine) compared with the prototype calcium channel antagonists. Additional clinical experience with these newer agents is required, however, before their role in the management of cardiovascular disorders can be fully delineated. The availability of sustained-release formulations of verapamil, diltiazem, nifedipine, felodipine, and nicardipine, as well as the recent marketing of calcium channel antagonists with relatively long half-lives (amlodipine and isradipine), makes once- or twice-daily dosing possible with most calcium channel blockers. However, selection of a particular agent will depend on several factors, including clinical efficacy, side effect profile, cost, and patient characteristics such as concomitant disease states and baseline hemodynamic status.

Aminoalkoxybenzenesulfonyl heterocyclic compounds, a novel class of calcium channel antagonists. Structure-activity relationship with a focus on fantofarone, SR 33557

Aminoalkoxybenzenesulfonyl heterocyclic compounds, a novel class of calcium channel antagonists. Structure-activity relationship with a focus on fantofarone, SR 33557

The effect of three classes of calcium-channel antagonists on polyinosinic: polycytidylic acid-induced fever

The effect of three classes of calcium-channel antagonists on polyinosinic: polycytidylic acid-induced fever

The effect of calcium antagonists on atrial natriuretic peptide (ANP) release from the rat heart during rapid cardiac pacing

The diuresis associated with rapid atrial rhythms is a well recognized clinical entity (Wood, 1963). Atrial natriuretic peptide (ANP) levels are elevated during rapid atrial rhythms (Hirata et al., 1987), including during rapid atrial pacing (Rankin et al., 1986; Schiebinger and Linden 1986; Walsh et al., 1987), and may contribute to the associated diuresis. Calcium channel antagonists are often used to treat atrial tachycardias but the effect this may have on ANP secretion and subsequent compensatory responses, such as a diuresis, is unknown. Reported here are experiments demonstrating that the increase in ANP secretion that accompanies rapid atrial pacing of the isolated perfused rat heart is abolished by calcium channel antagonists. This effect is not limited to a single class of calcium channel antagonists and could be demonstrated with Verapamil and Nifedipine. Although extrapolation to the in vivo situation should always be done with care, the results reported here contribute towards clarifying the effect of the calcium channel antagonists on the ANP response to rapid heart rates.

Characterization of binding sites for two classes of calcium channel antagonists in human forebrain

1,4-Dihydropyridine ([ 3H]PN200-110) and phenylalkylamine ([ 3H](−)D-888) bound with high affinity to human brain cortex homogenates. The ligand selectivity pattern indicates that [ 3H]PN200-110 binding was inhibited by related 1,4-dihydropyridine analogues but not phenylalkylamines. On the other hand, phenylalkylamines were potent inhibitors of [ 3H](−)D-888 binding in human brain. The radioautographic distribution of [ 3H]PN200-110 and [ 3H](−)D-888 binding sites demonstrates that 1,4-dihydropyridine and phenylalkylamine sites were similarly distributed in human forebrain.

Crystal structures and pharmacological activity of calcium channel antagonists: 2,6-dimethyl-3,5-dicarbomethoxy-4-(unsubstituted, 2-methyl-, 4-methyl-, 3-nitro-, 4-nitro-, and 2,4-dinitrophenyl)-1,4-dihydropyridine.

The molecular structures of 2,6-dimethyl-3,5-dicarbomethoxy-4-phenyl-1,4-dihydropyridine and the 3-methyl-, 4-methyl-, 3-nitro-, 4-nitro-, and 2,4-dinitrophenyl derivatives were determined by X-ray diffraction methods. The dihydropyridine ring in each of the compounds exists in a boat-type conformation. However, the degree of ring puckering varies among the compounds. The observed ring distortions were found to be influenced to a great extent by the position of the substituent in the 4-phenyl ring and the conformation about the interring bond. The distortion at the apical nitrogen of the dihydropyridine ring was found to be linearly related to that at the apical tetrahedral carbon. A correlation was observed between the pharmacological activities of this class of calcium channel antagonists, determined by their ability to inhibit the Ca2+-dependent muscarinic mechanical responses of guinea pig ileal longitudinal smooth muscle, and the magnitude of the 1,4-dihydropyridine ring puckering; the more active compounds exhibited the smallest degree of ring distortion from planarity.