Calcium Channel Antagonist Activity Research Articles

Structural Modifications of Nimodipine Lead to Novel PDE1 Inhibitors with Anti-pulmonary Fibrosis Effects.

Our previous research demonstrated that phosphodiesterase-1 (PDE1) could work as a potential target against idiopathic pulmonary fibrosis. Nimodipine, a calcium antagonist commonly used to improve hypertension, was reported to have inhibition against PDE1. Herein, a series of nimodipine analogues were discovered as novel selective and potent PDE1 inhibitors after structural modifications. Compound 2g exhibited excellent inhibitory activity against PDE1C (IC50 = 10 nM), high selectivity over other PDEs except for PDE4, and weak calcium channel antagonistic activity. Administration of compound 2g exhibited remarkable therapeutic effects in a rat model of pulmonary fibrosis induced by bleomycin and prevented myofibroblast differentiation induced by TGF-β1. The expressions of PDE1B and PDE1C were found to be increased and concentrated in the focus of fibrosis. Compound 2g increased the levels of 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) in the lungs of rats with pulmonary fibrosis, supporting the fact that the anti-fibrosis effects of 2g were through the regulation of cAMP and cGMP.

A review on 1,4-dihydropyridines as anti-tuberculosis agent

1,4-dihydropyridines show various pharmacological scheme such as calcium channel antagonist Activity, antitumor, anti-tubercular scheme, analgesic scheme, and many more.These showed incredible movement against mycobacterium tuberculosis with least inhibitory focus and furthermore showed moderately low cytotoxicity. 1,4-dihydropyridines (DHP) are the most generally used kind of calcium channel blocker in hypertension. DHP act with the aid of binding to amino acid residues in two adjoining S6 segments plus the intervening S5 segment. They are a pharmacologically active substance and are regarded as a significant class of organic chemicals for their Ca chamber modular action. I,4-DHP Shows various pharmacological activity such as antihypertensive, antianginal, vasodilator and cardiac depressants. Also the structure–activity relationship (SAR) of DHPs as antituberculosis agent was reviewed,discussed and summarized.

Pharmacological Modulation of Smooth Muscles and Platelet Aggregation by Psidium cattleyanum.

Traditionally, in the Southern Asian countries, Psidium cattleyanum is a widely used plant for the management of various ailments such as gastrointestinal, respiratory, and cardiac disorders, but it lacks proof on a scientific basis, and therefore, this is the major emphasis of the current research work. Crude extract of Psidium cattleyanum (Pc.Cr) was preliminary analyzed for the presence of different classes of bioactive molecules. The aqueous and dichloromethane fractions of Pc.Cr were subjected to in vitro and in vivo studies. It was applied at variable concentrations (0.1–10 mg/ml) to isolated rabbit jejunum to investigate spasmolytic effect. Concentration dependent curves of calcium were constructed to check the calcium channel antagonistic activity. For the evaluation of tracheorelaxant activity, isolated tracheal tissue was treated with High-K+ (80 mM) and carbachol (CCh) and then challenged cumulatively with Pc.Cr. To study the antidiarrheal effect of the plant extract, castor oil-induced diarrhea model was adopted. For evaluation of the hypotensive effect of Pc.Cr, it was given intravenously to preanesthetized normotensive rats, and the response was recorded using pressure transducer. Platelet rich plasma was used for the assessment of the antiplatelet activity when challenged with purinergic and adrenergic agonists. Concentration-dependent inhibition of spontaneous and High-K+ mediated contractions in isolated jejunum was observed by the application of Pc.Cr. Contractions induced in isolated tracheal tissue by High-K+ and CCh were inhibited by application of Pc.Cr to these tissues. Similarly, application of Pc.Cr to High-K+ and phenylephrine (PE) treated aortic strips resulted in vasodilation. Platelet aggregation inhibition was shown by Pc.Cr against adenosine diphosphate (ADP) only. The antidiarrheal effect was observed as a reduction in the total number of feces in Pc.Cr-treated mice when given castor oil. Dose-dependent hypotension was seen in normotensive rats when treated with Pc.Cr intravenously. This study showed the spasmolytic, tracheorelaxant, vasodilator, platelet aggregation inhibitory, antidiarrheal, and hypotensive activities of P. cattleyanum which may be due to the blockage of calcium channels, but the involvement of any other pathway cannot be ignored.

Facile preparation of 3-substituted 2-quinazolinones via electrogenerated base

A new series of 3,4-disubstituted quinazolin-2-ones, with potential T-type calcium channel antagonist activity, and new 4-methylene-quinazolin-2-ones, promising catalysts as N-heterocyclic olefins, have been prepared in good yield by a simple reaction between 2-aminobenzophenone, or 2-aminoacetophenone, and cyanomethyl anion electrogenerated by acetonitrile reduction at a graphite electrode, followed by the addition of different organic isocyanates and subsequent heterocyclization.

Synthesis and calcium channel antagonist activity of 1,4-dihydropyridine derivatives containing 4-nitroimidazolyl substituents.

Alkyl, cycloalkyl and arylakyl ester analogues of nifedipine (CAS 21829-25-4), in which the ortho-nitro phenyl group at position 4 is replaced by 1-methyl-4-nitro-5-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonists using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle. The results for the symmetrical esters showed that increasing the length of methylene chain in C-3 and C-5 ester substituents for more than two methylene units (n > 1) decreases activity. In the phenylalkyl ester series increasing the length of methylene chain increases activity. In the series of unsymmetrical phenylalkyl esters (R2 = Me or Et) increasing the length of the methylene chain decreases activity. The results demonstrate that most of the compounds had similar activity to the reference drug nifedipine. Among symmetrical diesters (methyl, ethyl and phenylpropyl derivatives) and among unsymmetrical series (benzyl methyl, benzyl ethyl and phenethyl ethyl derivatives) were more active than the reference drug nifedipine. The unsymmetrical phenethyl ethyl derivative was the most potent antagonist tested. The structure-activity data indicate that the 4-(1-methyl-4-nitro-5-imidazolyl) moiety, bioisoester of 2-nitro-phenyl moiety, is as good as other nitro-imidazolyl moieties.

Synthesis and calcium channel antagonist activity of new 1,4-dihydropyridine derivatives containing dichloroimidazolyl substituents.

A group of dialkyl, dicycloalkyl and diaryl ester analogues of nifedipine (CAS 21829-25-4), in which the ortho-nitrophenyl group at position 4 is replaced by a 4,5-dichloroimidazolyl substituent, were synthesized and evaluated as calcium channel antagonists using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle. The results for the symmetrical esters in alkyl esters series showed that increasing the length of the methylene chain in C3 and C5 ester substituents (from n = 0 to n = 2) increased the activity. When increasing of the length was accompanied by increase of the hindrance, the activity decreased. In the unsymmetrical diester series, the results showed when R1 is a small substituent (R1 = Me), increasing of the lipophilic property in R2 substituent increases the activity if this high lipophilicity is not accompanied by steric hindrance. The results demonstrate that in the unsymmetrical series, several compounds (benzyl methyl, benzyl isopropyl and cyclohexyl ethyl) had activity similar to that of the reference drug nifedipine. In symmetrical diesters compounds, the most active compound was the diphenethyl ester derivative being more active than nifedipine. These structure-activity data indicate that the 4-(4,5-dichloroimidazolyl) moiety is the bioisoester of 3-nitrophenyl and 2,3-dichlorophenyl moieties.

Synthesis and Calcium Channel Antagonist Activity of New 1,4-Dihydropyridine Derivatives Containing Lipophilic 4-Imidazolyl Substituents

A group of cycloalkyl and aryl ester analogues of nifedipine (CAS 21829-25-4), in which the ortho-nitrophenyl group at position 4 is replaced by a 2-phenyl-4(5)-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonist using the high K+ contraction of guinea-pig ileal smooth muscle. The results for the symmetrical esters in cycloalkyl and aryl esters showed that increasing the length of the methylene chain in C3 and C5 ester substituents (from n = 0 to n = 3) increased activity. A comparison of the effect of cyclohexyl relative to phenyl substituent showed that cyclohexyl derivatives were more active than phenyl derivatives. In contrast to symmetrical derivatives, comparison of the activities of asymmetrical esters showed that phenyl derivatives were more active than cycloalkyl derivatives. The results demonstrate that compounds 5a, 8a, 8l and 8n had similar activity to and compounds 5b, 5c, 5d and 5i were more active than the reference drug nifedipine. The structure-activity data indicate that the 4-(2-phenyl-4(5)-imidazolyl) moiety is a bioisoester of the o-nitro group of nifedipine.

4-Difluoro-substituted Phenyl-5-oxo-hexahydroquinoline Derivatives and Their Effects on Calcium Channels

Twenty new methyl(ethyl) 2,6,6- or 2,7,7-trimethyl-5-oxo-4-(disubstituted phenyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylates and ten new N,N-diethyl-2,6,6- or 2,7,7-trimethyl-5-oxo-4-(disubstituted phenyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide derivatives have been synthesised and screened for their calcium channel antagonistic activity. The compounds were synthesised by the Hantzsch reaction. Calcium antagonistic activities of the compounds were determined by the tests performed on isolated rat ileum and rat thoracic artery.

Synthesis, cytotoxicity and calcium antagonist activity of novel imidazolyl derivatives of 1,8-acridinediones

A series of novel imidazolyl derivatives of fully and partially hydrogenated 1,8-acridinediones were synthesized and assessed for their cytotoxic activity on four different human cancer cell lines (HeLa, MCF-7, LS-180, and Raji cells). Although being inactive on LS-180 and Raji cell lines, the compounds showed weak to moderate anti-tumor activities on other cell lines and their IC50 ranged from 31.7 to more than 100 μM. Among the synthesized compounds 12b, 13b, 12c and 13c, bearing an electronattracting substituent on the imidazole ring, and 12f and 13f, with a benzyl substituent, showed higher activities. Furthermore, the calcium channel antagonist activity of the derivatives, an undesired effect when these compounds are used as anti-tumor agents, was much lower than that of Nifedipine, a reference antagonist. Imidazolyl derivatives of 1,8-acridinedione represent an interesting template, showing promising biological properties. Further investigation on this chemical scaffold could potentially lead to the discovery of cytotoxic agents with low calcium channel blocking activity.

Multi-Target-Directed Ligands in Alzheimer's Disease Treatment

Among the various drug discovery methods, a very promising modern approach consists in designing multi-target-directed ligands (MTDLs). This methodology has been specifically developed for treatment of disorders with complex pathological mechanisms. One such disorder is Alzheimer's disease (AD), currently the most common multifactorial neurodegenerative disease. AD is related to increased levels of the amyloid β peptide (Aβ) and the hyperphosphorylated tau protein, along with loss of neurons and synapses. Moreover, there is some evidence pointing to the role of oxidative stress, metal ion deregulation, inflammation and cell cycle regulatory failure in its pathogenesis. There are many attractive targets for the development of anti-AD drugs, and the multi-factor nature of this disease calls for multi-target-directed compounds which can be beneficial for AD treatment. This review presents the discovery of dualand multi-acting anti-AD drug candidates, focusing on the novel design strategy and the compounds it yields - particularly hybrids obtained by linking structurally active moieties interacting with different targets. The first group of compounds includes cholinesterase inhibitors acting as dual binding site inhibitors and/or inhibitors with additional properties. These compounds are characterized by increased potency against acetylcholinesterase (AChE) and Aβ plaque formation with additional properties such as antioxidant activity, neuroprotective, and metal-complexing property, voltage-dependent calcium channel antagonistic activity, inhibitory activity against glutamate-induced excitotoxicity, histamine H(3) receptor antagonism, cannabinoid CB(1) receptor antagonism and β-secretase (BACE1) inhibition. A novel class of compounds represents the combination of dual BACE1 inhibitors with metal chelators, and dual modulators of γ-secretase with peroxisome proliferator-ativated receptor γ (PPARγ). We have reviewed the latest reports (2008-2011) presenting new multi-target-directed compounds in Alzheimer's disease treatment.

ChemInform Abstract: Synthesis and Calcium Channel Antagonist Activity of New Symmetrical and Asymmetrical 4‐[2‐Chloro‐2‐(4‐chloro‐6‐methyl‐2‐oxo‐2H‐pyran‐3‐yl)vinyl]‐substituted 1,4‐Dihydropyridines.

AbstractA variety of new symmetrically and unsymmetrically substituted title dihydropyridines (V) and (IV), resp., are synthesized via modified Hantzsch reactions and evaluated for their calcium channel blocking activity.

ChemInform Abstract: Design, Synthesis and Evaluation of Cytotoxicity of Novel Chromeno[4,3‐b]quinoline Derivatives.

AbstractSome of the title compounds (III) (15 examples) show moderate cytotoxic activity on human cancer cell lines and, at the same time, very low calcium channel antagonistic activity.

Synthesis and calcium channel antagonist activity of new symmetrical and asymmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-substituted 1,4-dihydropyridines

New symmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-substituted 1,4-di-hydropyridines were synthesized in moderate to good yields via the modified Hantzsch reaction of β-dicarbonyl compounds with (Z)-3-chloro-3-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)acrolein in the presence of an excess amount of NH4OAc. Also, the reaction of β-dicarbonyl compounds with (Z)-3-chloro-3-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)acrolein in the presence of enamino esters and ketones was performed, and asymmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-substituted 1,4-dihydropyridines were obtained in moderate to good yields at room temperature. The calcium channel blocking activity of these compounds was assessed. They demonstrated moderate to weak effects, although one compound had a comparable effect (IC50 =1.40×10−7 M) with respect to the reference drug Nifedipine.

Two 1,4-dihydropyridine derivatives with potential calcium-channel antagonist activity

The title compounds, benzyl 4-(3-chloro-2-fluorophenyl)-2-methyl-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate, C(23)H(19)ClFNO(3), (I), and 3-pyridylmethyl 4-[2-fluoro-3-(trifluoromethyl)phenyl]-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, C(26)H(24)F(4)N(2)O(3), (II), belong to a class of 1,4-dihydropyridines whose members sometimes display calcium modulatory properties. The 1,4-dihydropyridine ring in each structure has a shallower than usual shallow-boat conformation and is nearly planar in (I). In each structure, the halogen-substituted benzene ring is oriented such that the halogen substituents are in a synperiplanar orientation with respect to the 1,4-dihydropyridine ring plane. The oxocyclopentene ring in (I) is planar, while the oxocyclohexene ring in (II) has a half-chair conformation, which is less commonly observed than the envelope conformation usually found in related compounds. In (I), the frequently observed intermolecular N-H···O hydrogen bond between the amine group and the carbonyl O atom of the oxocyclopentene ring of a neighbouring molecule links the molecules into extended chains; there are no other significant intermolecular interactions. By contrast, the amine group in (II) forms an N-H···N hydrogen bond with the pyridine ring N atom of a neighbouring molecule. Additional C-H···O interactions complete a two-dimensional hydrogen-bonded network. The halogen-substituted benzene ring has a weak intramolecular π-π interaction with the pyridine ring. A stronger π-π interaction occurs between the 1,4-dihydropyridine rings of centrosymmetrically related molecules.

Synthesis and calcium channel antagonist activity of novel 1,4-dihydropyridine derivatives possessing 4-pyrone moieties

New 1,4-dihydropyridine derivatives were synthesized by introducing 4-pyrone ring systems at the 4-position of the dihydropyridine nucleus. These compounds were obtained according to Hantzsch reaction. 4-Pyrone carbaldehydes: 4-(4-oxo-6-phenyl-4H-pyran-2-yl)benzaldehyde 4a, 4-(6-methyl-4-oxo-4H-pyran-2-yl)benzaldehyde 4b, 4-oxo-6-phenyl-4H-pyran-2-carbaldehyde 7a, and 6-methyl-4-oxo-4H-pyran-2-carbaldehyde 7b were synthesized and used in these reactions. Then, the calcium channel blocking activity of some of these compounds were evaluated in which they showed weak effects.

Design, Synthesis and Evaluation of Cytotoxicity of Novel Chromeno[4,3‐b]quinoline Derivatives

In the present work 15 new 1,4-dihydropyridines (DHPs) bearing a coumarin ring were synthesized and assessed on 4 different human cancer cell lines (HeLa, K562, LS180, and MCF-7). Although, all the derivatives were inactive on LS180 cell line, the results on other cells showed that these compounds had weak to moderate antitumoral activities and their IC(50) ranged from 25 to >100 µM. Among the synthesized compounds, 7-(2-nitrophenyl)-8,9,10,12-tetrahydro-7H-chromeno[4,3-b]quinoline-6,8-dione (6a) demonstrated the highest activity (IC(50) range in different cell lines: 25.4-58.6 µM). Furthermore, the calcium channel antagonist activity of the derivatives, an undesired effect when these compounds are used as antitumoral agents, was much lower than nifedipine, a reference antagonist. In conclusion, this group of compounds seems to have promising biological properties and further investigation on this group could potentially lead to the discovery of cytotoxic agents with low calcium channel blocking activity.

Gut modulatory and antiplatelet activities of Viscum cruciatum

Viscum cruciatum Sieber (Viscaceae) is widely used in folk medicine for various gastrointestinal and inflammatory disorders. The crude extract of Viscum cruciatum (VCr), which tested positive for alkaloids, flavonoids, coumarins, saponins, sterols, tannins, and terpenes, caused concentration-dependent (0.01–3.0 mg/mL) relaxation of spontaneous and K+ (80 mM)-induced contractions of isolated rabbit jejunum, similar to that caused by verapamil. VCr shifted the Ca2+ concentration–response curves to the right with suppression of the maximum response, like verapamil. In guinea-pig ileum preparations, VCr caused atropine-sensitive spasmogenic effects. When tested for its effect on human platelets, VCr inhibited the adrenaline and adenosine 5′-diphosphate (ADP)-induced human platelet aggregation at the concentration range of 0.3–1.2 mg/mL. These observations indicate the presence of spasmogenic, spasmolytic, and antiplatelet activities in Viscum cruciatum mediated through cholinergic and calcium channel antagonist activities along with the blockade of adrenergic and ADP receptors, respectively, which explains its medicinal use in gut motility and inflammatory disorders.

Condensed 1,4-dihydropyridines with various esters and their calcium channel antagonist activities

New alkyl 2,6,6-(2,7,7)-trimethyl-4-(2-fluoro-3-chloro-5-trifluoromethylphenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylates and 9-(3-chloro-2-fluoro-5-trifluoromethylphenyl)-6,6(7,7)-dimethyl-6,7-dihydrofuro[3,4- b]quinoline-1,8-diones have been synthesised and their calcium antagonistic activities on isolated rabbit sigmoid colon have been investigated and compared with Nifedipine. The investigation examined the influence of ester groups in the 3-position of the HHQ ring and the 2-methoxyethyl analogs were found to be the most active derivatives.

Lipophilic 2-(4-chlorophenyl)-4-thiazolyl-1,4-dihydropyridines: synthesis, calcium channel antagonist activity, and protection against pentylenetetrazole-induced seizure

A series of alkyl, cycloalkyl, and aryl esters of nifedipine in which the o-nitrophenyl group at position 4 is replaced by 2-(4-chlorophenyl)-4-thiazolyl substituent were synthesized and evaluated for their calcium channel antagonist activities using isolated ileum of guinea pig. The anticonvulsant activity of test drugs was also assessed in pentylenetetrazole (PTZ)-induced seizure in male Naval Medical Research Institute (NMRI) mice model. The results showed that although all compounds were at least 100 times less active than the reference drug nifedipine in terms of calcium channel antagonist activity, nevertheless all compounds showed considerable anticonvulsant activity. A new series of alkyl, cycloalkyl and aryl substituted 4-chlorophenylthiazolyl–1,4-dihydropyridines were synthesized and tested for calcium channel inhibitory and anticonvulsant activities.

ChemInform Abstract: Synthesis, QSAR and Calcium Channel Antagonist Activity of New 1,4‐Dihydropyridine Derivatives Containing 1‐Methyl‐4,5‐dichloroimidazolyl Substituents.

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