Potent Calcium Antagonist Research Articles

Effects of MgSO4 on inhibiting Nod-like receptor protein 3 inflammasome involve decreasing intracellular calcium

BackgroundNod-like receptor protein 3 (NLRP3) inflammasome is a multiprotein complex composed of NLRP3, caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain. Activation of NLRP3 inflammasome leads to interleukin-1β (IL-1β) upregulation and pyroptosis, a proinflammatory cell death characterized by increased cell size. Of note, calcium signaling is crucial for NLRP3 inflammasome activation. This study elucidated the effects of magnesium sulfate (MgSO4), a potent calcium antagonist, on modulating NLRP3 inflammasome. Materials and methodsTHP-1 cells, the human monocytic leukemia cell line, were treated with lipopolysaccharide (LPS, 1 μg/ml) plus nigericin (5 μM) (the LPS + Nig group) and LPS plus nigericin plus MgSO4 (20 mM) [the LPS + Nig + M(20)] to facilitate investigations. Levels of IL-1β, pyroptosis, and NLRP3 inflammasome induction as well as intracellular calcium were assayed. ResultsIL-1β concentration of the LPS + Nig + M(20) group was significantly lower than the LPS + Nig group (P = 0.001). Cell size of the LPS + Nig + M(20) group was significantly smaller than the LPS + Nig group (P < 0.001). Level of pyroptotic cell death of the LPS + Nig + M(20) group was significantly lower than the LPS + Nig group (P = 0.004). NLRP3 mRNA and protein concentrations of the LPS + Nig + M(20) group were also significantly lower than the LPS + Nig group (P = 0.021 and P < 0.001). Similarly, apoptosis-associated speck-like protein containing a caspase recruitment domain speck formation ratio and caspase-1 concentration of the LPS + Nig + M(20) group were significantly lower than the LPS + Nig group (both P < 0.001). The change in intracellular calcium level of the LPS + Nig + M(20) group was significantly smaller than the LPS + Nig group (P = 0.001). ConclusionsMgSO4 inhibits NLRP3 inflammasome, IL-1β upregulation, and pyroptosis. The mechanism is consistent with decreased intracellular calcium levels.

Design and synthesis of novel 4-substituted 1,4-dihydropyridine derivatives as hypotensive agents

Calcium-channel blockers have an important role in the treatment of several cardiovascular disorders. Derivatives of 1,4-dihydropyridines are one of the most potent calcium antagonists. In this study a series of novel 1,4-dihydropyridine calcium channel blockers of general formula diethyl 4-(4-substituted phenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate were synthesized and tested for hypotensive activity, including electrocardiographic and effect on heart rate. Compound diethyl 4-(4-benzyloxy phenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (DHP I) and diethyl 4-(2-(2-chlorobenzyloxy) phenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (DHP III), were the most potent in this series. All synthesized compounds lowered rat blood pressure significantly in comparison with DMSO as control and nifedipine was used as positive control.

Synthesis and Myorelaxant Activity of Fused 1,4‐Dihydropyridines on Isolated Rabbit Gastric Fundus

Abstract Strategy, Management and Health Policy Preclinical Research In the present study, 25 novel condensed 1,4‐dihydropyridine (DHP) derivatives bearing cyclopentane, cyclohexane, or tetrahydrothiopene ring with a bulky and lipophilic moiety (3‐pyridylmethyl) in the ester group were synthesized via a modified Hantzsch reaction, and their calcium channel modulator activities were assayed on isolated rabbit gastric fundus smooth muscle strips. To evaluate the myorelaxant effects of the compounds, the maximum relaxant response (Emax) and pD 2 values were calculated. The results indicated that all compounds produced concentration‐dependent relaxation and the introduction of five‐ or six‐membered rings to the DHP nucleus and 3‐pyridiylmethyl moiety to the ester group led to potent calcium antagonists.

Synthesis of Novel 4-[1-(4-fluorobenzyl)-5-imidazolyl] Dihydropyridines and Studying their Effects on Rat Blood Pressure.

Calcium-channel blockers have an important role in the treatment of several cardiovascular disorders. Derivatives of 1, 4-dihydropyridine are one of the most potent calcium antagonists. In this study four novel 1, 4-dihydropyridine calcium channel blockers were synthesized and their hypotensive properties were investigated in male rats. Four 1, 4-dihydropyridines bearing 1-(4-fluorobenzyl)-5-imidazolyl substituent at 4 position (5a-d) were synthesized and tested for hypotensive activity in male rats. The animal was anaesthetized and the right jugular vein was cannulated for the administration of test agents. The left carotid artery was cannulated and connected to a pressure transducer for continuous monitoring of arterial blood pressure. All synthesized compounds lowered rat blood pressure significantly in comparison with DMSO as vehicle and nifedipine as positive control. The hypotensive effects of all compounds were less than that of nifedipine at 2 and 4 mg/kg (P< 0.05). The order of their effects on mean arterial blood pressure (MABP) was 5b>5c>5a>5d at dose of 4 mg/kg (P< 0.05). All compounds tested increased heart rate in comparison with DMSO (P< 0.05). The chronotropic effect of nifedipine was significantly less than synthesized compounds at dose of 4 mg/kg (P< 0.01). The results showed that these novels 1, 4-dihydropyridines decreased mean arterial blood pressure (MABP) significantly, while increased heart rate in rat.

Protective effects and mechanism of tetramethylpyrazine against lens opacification induced by sodium selenite in rats

Tetramethylpyrazine (TMP), extracted from the Chinese herbal medicine Ligusticum wallichii franchat (chuan xiong in Chinese), is a potent anti-free radical and calcium antagonist. Correspondingly, two important hypotheses in the causation of cataracts are free radical toxicity and calcium ion overload. In this study we investigated the effect of TMP on lens opacification induced by sodium selenite in rats, addressing the potential of TMP eye drops to prevent and treat cataracts. Results showed that the extent of lens opacification in the untreated Normal Control group (NC group) was significantly less than that of selenite-injected untreated rats (MC group) on days 3, 5, 7 and 10 ( p < 0.001), while TMP treated selenite-injected rats (TMP group) had less lens opacification than the MC group on days 3, 5, 7 and 10 ( p < 0.05). Compared with the NC group, the MC group had significantly decreased activity of super-oxide dismutase (SOD), glutathione peroxidase (GSH-PX) and catalase (CAT) and significantly elevated malondialdehyde (MDA) and calcium ion content ( p < 0.001). Compared with the MC group, the activity of (SOD), (GSH-PX) and (CAT) were significantly higher while (MDA) and calcium ion levels were significantly lower in the TMP group at all time points ( p < 0.01). The findings demonstrate that the selenite-induced cataract rat models were successfully built and the TMP eye drops can delay lens opacification induced by sodium selenite in rats. The mechanism by which TMP preserves lens transparency from selenite treated animals is associated with the lenses’ ability to maintain normal levels of activity of SOD, GSH-PX and CAT and normal concentrations of MDA and calcium ion.

In vivo Receptor Occupancy and Plasma Concentration of Pranidipine, a Potent and Long-Acting Dihydropyridine Calcium Antagonist

The occupancy of 1,4-dihydropyridine (DHP) receptors by pranidipine was characterized in tissues of spontaneously hypertensive rats (SHR). Oral administration of pranidipine (1 and 3 mg/kg) in SHR produced significant (26–67%) decreases in the number of specific (+)-[³H]PN 200-110 binding sites (B_max) with 2- to 4-fold increases in the apparent dissociation constant (K_d) in myocardial tissues at 1, 3 and 6 h later. In these rats, there was a reduction (16–37%) of B_max in cerebral cortical (+)-[³H]PN 200-110 binding. Occupancy of myocardial DHP receptors after oral administration of pranidipine correlated well with its plasma concentration. Oral administration of nifedipine (10 mg/kg) in SHR caused significant increase in K_d values for (+)-[³H]PN 200-110 binding in myocardium and cerebral cortex at 1 h later. In vivo specific (+)-[³H]PN 200-110 binding in particulate fractions of SHR aorta was markedly (59–78%) reduced at 1, 3 and 12 h after oral administration of pranidipine (3 mg/kg), while myocardial (+)-[³H]PN 200-110 binding was decreased by 46–48% at 1 and 3 h later. In these rats, there was a significant decrease (34%) in cerebral cortical (+)-[³H]PN 200-110 binding at 3 h later. In contrast, nifedipine administration produced a similar degree of reduction (71–84%) of in vivo (+)-[³H]PN 200-110 binding in the myocardium, aorta and cerebral cortex. It is concluded that pranidipine may exert more selective and sustained occupation in vivo of DHP receptors in vascular tissues of SHR than in myocardial and brain tissues.

New calcium antagonists: synthesis, X-ray analysis, and smooth muscle relaxing effect of 3-[O-(Benzyl-substituted)-oximino-ethers]-hexahydroazepin-2,3-diones

A series of new Z and E 3-[O-(benzyl-substituted)-oximino-ether]-hexahydroazepin-2,3-diones was prepared from the corresponding hexahydroazepin-2,3-diones and examined as smooth muscle relaxants. E and Z structures were assigned by NMR analysis and confirmed for 16 (E and Z) by an X-ray diffraction using synchrotron radiations. The nitrobenzyl derivative 16 was the most potent in vitro as relaxant of rat trachea precontracted with acetylcholine. The E isomer 16b was more potent than the Z isomer 16a . E isomer 16b is more potent than aminophylline to relax both rat trachea and human bronchus.This derivative acts mainly by inhibiting cellular influx of extracellular calcium since it inhibits potently and dose-dependently the contractions of rat trachea to high concentrations of KCl and to CaCl2 in a depolarizing medium. It appears to act weakly by inducing cGMP and cAMP synthesis. Moreover, its relaxing activity is not related to an inhibition of phosphodiesterases, to opening of potassium channels or to induction of prostaglandin synthesis. Therefore, 16b appears to work mainly as a potent calcium antagonist.

Effects of Intracellular Calcium Reduction by Dantrolene on Prevention/Treatment of Ischemic Stroke.

BACKGROUND: It has been suggested that cerebral blood vessels and brain cells might depend more on intracellular calcium than extracellular calcium to modulate intracellular free calcium concentrations, [Ca(2+)](i). METHODS AND RESULTS: A potent intracellular calcium antagonist, dantrolene, was used to prevent the ischemic stroke induced in the rat model. It was found that treatment of rats with dantrolene at -1 hour and +1 hour after 60 minutes of ischemic insult prevented by the formation of cortical necrosis 98% and 85%, respectively. Further, the [Ca(2+)](i) of embryonic aorta cells was markedly reduced, and cAMP of the same cultured cells were significantly increased by dantrolene treatment. CONCLUSIONS: These results indicate that ischemic stroke is preventable by dantrolene through reduction of [Ca(2+)](i) and increase of cAMP.

Studies on the chemistry of thienoannelated o,n‐ and s,n‐containing heterocycles. 16. Synthesis of some thieno[1,4]thiazine derivatives with potential calcium antagonistic activity

AbstractSubstituted thieno[1,4]thiazine derivatives have been synthesized. They are thienoanalogues of compound 3 [2], a potent cerebral protectant and calcium antagonist. Research activities concentrate on the preparation of structurally modified compounds of 3 to minimize its undesirable symptoms.

Synthesis and Calcium Channel-Modulating Effects of Alkyl (or Cycloalkyl) 1,4-Dihydro-2,6-dimethyl-3-nitro-4-pyridyl-5-pyridinecarboxylate Racemates and Enantiomers

A group of racemic alkyl (or cycloalkyl) 1,4-dihydro-2,6- dimethyl-3-nitro-4-(2-, 3-, or 4-pyridyl)-5-pyridinecarboxylate isomers (6-14) were prepared using a modified Hantzsch reaction that involved the condensation of nitroacetone with an alkyl (or cycloalkyl) 3-aminocrotonate and 2-, 3-, or 4-pyridinecarboxaldehyde. Determination of their in vitro calcium channel-modulating activities using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays showed that the 2-pyridyl isomers acted as dual cardioselective calcium channel agonists (GPLA)/smooth muscle selective calcium channel antagonists (GPILSM). In contrast, the 3-pyridyl and 4-pyridyl isomers acted as calcium channel agonists on both GPLA and GPILSM. In the C-4 2-pyridyl group of compounds, the size of the C-5 alkyl (or cycloalkyl) ester substituent was a determinant of GPILSM antagonist activity where the relative activity profile was cyclopentyl and cyclohexyl > t-Bu, i-Bu, and Et > MeOCH2CH2 > Me. The point of attachment of the C-4 pyridyl substituent was a determinant of GPLA agonist activity where the potency order was generally 4- and 3-pyridyl > 2-pyridyl. (+)-Cyclohexyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-pyridyl)-5- pyridinecarboxylate [(+)-14a] was a less potent calcium antagonist (IC50 = 5.27 x 10(-6) M) than the (-)-enantiomer (IC50 = 7.48 x 10(-8) M) on GPILSM. In the GPLA assay, (+)-14a exhibited a much more potent agonist effect (EC50 = 8.45 x 10(-6) M) relative to the marginal agonist effect produced by (-)-14a. The C-4 2-pyridyl compounds (enantiomers) constitute a novel type of 1,4-dihydropyridine calcium channel modulator that could provide a new drug design concept directed toward the treatment of congestive heart failure, and for use as probes to study the structure-function relationships of calcium channels.

How to standardize vasomotor tone in serial studies based on quantitation of coronary dimensions?

In patients with coronary artery disease including those after coronary bypass graft operation and heart transplantation intervention studies based on serial quantitative coronary angiography, in part combined with intravascular ultrasound, are of increasing relevance. Since vasomotor tone of epicardial coronary arteries is influenced by a variety of factors, angiographic follow-up studies require standardization of coronary tone by induction of maximal dilation. We reviewed the effects of the most potent coronary vasodilatory drug groups, calcium antagonists and nitrocompounds, on coronary diameters. Intravenous or intracoronary injections of verapamil, diltiazem, nifedipine, nicardipine, and nisoldipine can cause profound coronary dilation which has been shown to be maximal with verapamil and nisoldipine. Shortcomings of calcium antagonists include short or unknown duration of action after bolus administration, severe drop in blood pressure, and lack of commercial availability of solutions for injection of many substances. Isosorbide dinitrate induces profound coronary dilation; however, after sublingual administration marked blood pressure decrease can occur, and the duration of action and ideal dose of intracoronary isosorbide dinitrate has not been investigated yet. Injections of molsidomine and its active metabolite, SIN-1, cause longlasting, reproducible, maximal coronary dilation, although only after a waiting period of at least 10 minutes; unfortunately, SIN-1 is only commercially available in France. Nitroglycerin induces reproducible maximal coronary dilation and is easy to administer sublingually or as intracoronary bolus injection with rapid onset of action and no major side effects. The short duration of action may require repeated administrations. To date, repeated intracoronary bolus injections of 0.1 mg nitroglycerin every 10 minutes seem to be the optimal known regimen for standardization of coronary vasomotor tone in serial angiographic studies. Further investigations in this field with old and new vasodilatory drugs are recommendable.

1,4-Dihydropyridines bearing a pharmacophoric fragment of lidoflazine

A series of 1,4-dihydropyridines bearing a pharmacophoric fragment of lidoflazine was synthesized. The compounds were evaluated for inotropic, chronotropic, and calcium antagonist activities. All compounds behave as inotropic and chronotropic agents, except for compounds 4b, 5a, and 5b, which exibit a rather weak calcium antagonism in vascular smooth muscle (like aorta). Compound 5b is about twofold more potent in decreasing both chronotropy and inotropy, while compound 5c is about fivefold more potent in decreasing inotropy than nifedipine. Moreover, compound 5b is the most potent calcium antagonist derivative of the series.

Synthesis of azido derivatives of semotiadil, a novel 1,4-benzothiazine calcium antagonist, for photoaffinity probes of calcium channels

Aliphatic and aromatic azido derivatives of semotiadil ( 1), a novel calcium antagonist with a 1,4-benzothiazine skeleton, were synthesized for developing photoaffinity probes of L type calcium channels. The azidophenoxy derivative 12 proved to be a potent calcium antagonist and its [ 3H]-labeled compound 16 would be a useful tool to clarify the binding sites of 1 to the calcium channels.

Modification of adrenergic reactivity in rat tail artery by dietary lipids and calcium channel antagonists

1. 1. The antiatherosclerotic activity of dihydropyridines (DHP), potent calcium antagonists, was studied with respect to prevention of hypercontractility of perfused rat tail arteries. 2. 2. Used for 1 month, atherogenic diet increased pressor responses to norepinephrine (NE) in Ca 2+ free physiological salt solution (PSS), and PSS containing Ca 2+. 3. 3. When nifedipine (NIF) or nitrendipine (NIT) was administered simultaneously with an atherogenic diet, the contractile activity of NE in Ca 2+-free PSS was attenuated. Moreover, vasoconstrictor responses to NE in PSS containing Ca 2+ were inhibited after 1-month treatment with NIT and nimodipine (NIM). 4. 4. NIF, NIT and NIM prevented atherosclerosis-induced vascular hyperreactivity to α-adrenoceptor agonists in rat tail artery.

Pyrrolo[2,1-c][1,4]benzothiazines: synthesis, structure-activity relationships, molecular modeling studies, and cardiovascular activity.

The synthesis and pharmacological evaluation of a series of pyrrolo[1,4]benzothiazine derivatives are described. These compounds, related to diltiazem, have been shown to be representative of a novel series of calcium channel antagonists. The IC50S for inhibition of [3H]nitrendipine binding calculated by radioreceptor assay on rat cortex and rat heart homogenates showed that some of the described compounds possess an affinity equal to or higher than those of the reference calcium antagonists verapamil and cis-(+)-diltiazem. Furthermore, the alteration of the benzothiazepinone system of diltiazem to the pyrrolo[1,4]benzothiazine system of the title compounds resulted in a clear-cut selectivity for cardiac over vascular tissue, as shown in functional studies. In fact comparison of calcium antagonist activity on guinea pig aorta strips with the negative inotropic activity, determined by using an isolated guinea pig left atrium, revealed that the compounds examined displayed higher selectivity than the reference standard, within a wide variation of data. A number of structure-activity relationship trends have been identified, and possible explanation is advanced in order to account for the observed differences in selectivity. Prerequisite for in vitro calcium channel-blocking activity is the presence of two pharmacophores, namely, the substitution at C-4 and the substitution on the pyrrole ring. Two of the tested compounds, 8b and 28a, were identified as potent calcium antagonists selective for cardiac over vascular tissue.

Heterocyclic guanidines as calcium antagonists

A series of 2-(1,1-diphenylalkylamino)-1,3-diazaheterocycles was prepared and evaluated as antagonists of L-type calcium channels. Of the eighteen derivatives in this series, tetrahydropyrimidine 6h and hexahydro-1,3-diazocine 6n were the most potent calcium antagonists, being essentially equipotent to both diltiazem ( 2) and amidine 5.

1-[[4-(Aminoalkoxy)phenyl]sulfonyl]indolizines: a novel class of calcium entry blockers. Relationships between chemical structure, stereoelectronic properties and anticalcic activity

The solid-state structures of a series of 1-[[4-(aminoalkoxy)phenyl]sulfonyl]indolizines have been determined by X-ray analysis. These molecules are known to be representative of a novel class of calcium entry blockers characterized by a new binding site associated with the L-type calcium channel. Previous 2-dimensional structure-activity relationship studies have shown that 1-sulfonylindolizines substituted in the 2 position by an isopropyl group and possessing an aralkylamine substructure were among the most potent calcium antagonists. A comparative study of the 3-dimensional X-ray structures and the electronic properties computed at the ab initio HF level of five 1-sulfonyl, 2-alkyl and 2-phenylindolizine calcium antagonists presenting different types of amine substructures indicates important similarities within the series. This has led us to propose the first pharmacophoric elements for this kind of compound.

Isosteric replacement in a series of β-substituted monophosphonate calcium antagonists

A series of β-substituted phosphonate derivatives was prepared by standard routes and the Ca ++ channel inhibitory properties of the compounds examined in rat brain and aorta. The results indicate the certain ester substituents can serve as effective phosphonate replacements. The most potent calcium antagonist identified from the series was the β-substituted hexanoyl ester derivative BMY-43011 ( 5f).

Comparison of a Calcium Antagonist, CD-349, with Nifedipine, Diltiazem, and Verapamil in Rabbit Spontaneously Beating Sinoatrial Node Cells

Effects of CD-349, a novel 1,4-dihydropyridine, and other calcium antagonists on membrane potentials in spontaneously beating and the membrane currents in voltage-clamped rabbit sinoatrial (SA) node cells were examined. CD-349 10(-8) M significantly decreased the maximum rate of depolarization and prolonged action potential duration (APD) and the cycle length (CL) without affecting action potential (AP) amplitude (APA) and maximum diastolic potential (MDP). CD-349 affected only the last part of pacemaker potential (phase 4 depolarization) and then lengthened the cycle. These effects of CD-349 became accentuated as the drug concentration increased. Sinus arrest occurred in two of five preparations at 10(-7) M, and occurred in all preparations at a concentration of 10(-6) M. The concentration inducing arrest of CD-349 was about one-tenth lower as compared with that of nifedipine. In voltage-clamped SA node cells, CD-349 in concentrations of 3 x 10(-8) and 10(-7) M decreased the slow inward current; the steady-state outward current and the hyperpolarization-activated inward current were also reduced, but less markedly. Nifedipine decreased the slow inward current, the potency of which was one third less than that of CD-349. Diltiazem and verapamil were weaker in prolonging cycle length and in inducing arrest as compared with CD-349 and nifedipine. These results suggest that CD-349 is a more potent calcium antagonist for decreasing pacemaker activity of rabbit SA node cells as compared with the other three calcium antagonists tested.

Synthesis and pharmacological study of new calcium antagonists, analogues of cinnarizine and flunarizine

Several phosphonic diethyl esters were synthesized and their calcium antagonistic activity evaluated in vitro. The diethyl phosphonate group was condensed on substituted [diphenylmethyl], [(2-benzofuranyl)phenylmethyl], [(4-(diphenylmethyl-1-piperazinyl) methyl], [4 (4-diphenylmethyl-1-piperazinyl methyl) phenylmethyl], and [4-(3-phenyl-2-propenyl)-1-piperazinyl methyl] groups. Despite the presence of the diethyl phosphonate moiety and the benzhydrylpiperazinyl group, both present in potent calcium antagonist structures, only 1 of the 19 synthesized compounds exhibited a calcium antagonistic profile.