Channel Blocking Activity Research Articles

Vasorelaxant Effect of a Newly Synthesized Dihydropyridine Ethyl Ester (DHPEE) on Rat Thoracic Aorta: Dual Mechanism of Action.

DHPEE is a newly synthesized compound by merging the key structural elements in an angiotensin receptor blocker (Telmisartan) with key structural elements in 1,4- dihydropyridine calcium channel blocker (Nifedipine). In this study, we examined dual calcium channel blocking and AT1 antagonist activity for DHPEE. The functional inhibitory characteristics of DHPEE were studied in vitro in rat thoracic aorta preparations precontracted by phenylephrine (1μM) or KCl (80μM) or Ang II in normal or calcium-free solutions. Concentration-dependent significant relaxation was observed in aortic rings precontracted with phenylephrine, KCl or Ang II. The tension increment produced by increasing external calcium was also reduced by DHPEE. DHPEE caused a marked decrease in the maximal contractile response of the vasoactive agents and shifted their concentration-response curves to the right. DHPEE possesses dual characteristics and cause vasorelaxation by blocking the L-type calcium channels and blocking Ang II receptors (AT1) in rat aortic smooth muscle.

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.

Antidiarrheal and antispasmodic activities of Vincetoxicum stocksii are mediated through calcium channel blockade

This study was carried out to explore the mechanism underlying antidiarrheal and antispasmodic activities of Vincetoxicum stocksii. The crude extract of V. stocksii provided 12-24% protection from castor oil-induced diarrhea at the dose of 300-1,000 mg/kg, similar to loperamide. In isolated rabbit jejunum preparations, V. stocksii caused inhibition of the spontaneous and high K+ (80 mM)-induced contractions, with respective EC50 values of 2.53 (1.65-3.90) and 0.95 mg/mL (0.63-1.42), similar to that caused by verapamil, suggesting the calcium channel blocking effect. Loperamide caused inhibition of spontaneous and high K+-induced contraction, with respective EC50 values of 8.59 (6.33-10.11) and 9.12 µM (7.33-12.81). The calcium channel blocking activity was further confirmed when pretreatment of the tissues with V. stocksii (1-3 mg/mL) caused a rightward displacement of the Ca++ concentrations response curves, similar to that produced by verapamil; constructed in Ca++ free medium. These data indicate that the crude extract of V. stocksii contains calcium channel blocking constituents that may possibly explain its medicinal use in hyperactive states of gut, such as, diarrhea and spasms.

Role of T-type calcium channel subunits in post-myocardial infarction remodelling probed with genetically engineered mice

Previous studies suggested that T-type Ca(2+)-current (I(CaT))-blockers improve cardiac remodelling, but all available I(CaT)-blockers have non-specific actions on other currents and/or functions. To clarify the role of I(CaT) in cardiac remodelling, we studied mice with either of the principal cardiac I(CaT)-subunits (Cav3.1 or Cav3.2) knocked out. Adult male Cav3.1- or Cav3.2-knockout (Cav3.1(-/-), Cav3.2(-/-)) mice and respective wild-type (WT) littermate controls were subjected to left anterior descending coronary artery ligation to create myocardial infarction (MI). Echocardiography and programmed electrical stimulation were performed at baseline and 4 weeks post-MI. At baseline, Cav3.1(-/-) mice had slowed heart rates and longer PR intervals vs. WT, but no other electrophysiological and no haemodynamic differences. Cav3.2(-/-) showed no differences vs. WT. Contractile indices (left ventricular fractional shortening and ejection fraction) decreased more post-MI in Cav3.1(-/-) mice than in Cav3.1(+/+) (e.g. by 34 and 29% for WT; 50 and 45% for Cav3.1(-/-), respectively; P < 0.05 for each). Cav3.1(-/-) mice had increased ventricular tachycardia (VT) inducibility post-MI (9 of 11, 82%) vs. WT (3 of 10, 30%; P < 0.05). Cav3.2(-/-) mice were not different in cardiac function or VT inducibility vs. WT. Quantitative polymerase chain reaction showed that Cav3.1 is the major I(CaT)-subunit and that no compensatory Cav3.2 up-regulation occurs in Cav3.1(-/-) mice. Cav3.1(-/-) and Cav3.2(-/-) mice had no mRNA expression for the knocked-out gene, at baseline or post-MI. Our findings suggest that, contrary to suggestions from previous studies with (imperfectly selective) pharmacological agents having T-type Ca(2+)-channel-blocking actions, elimination of Cav3.1 expression leads to impaired cardiac function and enhanced arrhythmia vulnerability post-MI, whereas Cav3.2 elimination has no effect.

Liposoluble constituents from Iodes cirrhosa and their neuroprotective and potassium channel-blocking activity

To study the chemical constituents of Iodes cirrhosa and evaluate their bioactivity. The compounds were isolated and purified by various kinds of column chromatography methods and their structures were determined by spectroscopic data analysis. Neuroprotective assay against serum deprivation induced SH-SYSY-JNK3 cell apoptosis was evaluated by MTr method while potassium channel-blocking activity was assayed in both non-specific and specific K+ channel-regulator screening models. Twenty-one compounds were obtained from an EtOAc portion of an ethanolic extract of the root of I. cirrhosa. Their structures were elucidated as 1beta, 3beta-dihydroxyurs-9(11),12-diene(1), bauerenyl acetate(2),3beta-hydroxy-11-oxo-olean-12-enyl palmitate(3), 3beta-acetoxy-urs-12-ene-11-one(4), betulinic acid(5), stigmasta-5, 22-diene-3beta-ol(6), 7beta-hydroxystigmasterol(7), stigmasta-5, 22diene-3beta-ol3-O-beta-D-glucopyranoside(8),scopoletin(9),scopolin(10),clovamide(11),methyl 3,5-di-O-caffeoylquinate(12),3,5-dicaffeoylquinic acid(13),2,6-dimethoxy-1,4-benzoquinone(14), protocatechualdehyde(15), vanillin(16), protocatechuic acid(17), vanillic acid(18),caffeic acid(19),azelaic acid(20),and succinic acid(21). Compound 3,4,6,9,10,14,15,18 and 20 showed neuroprotective activities against serum deprivation induced SH-SYSY-JNK3 cell apoptosis at a concentration of 1.0 x 10(6) mol x L(1) with relative protection rates of 177%, 144%, 137%, 137%, 143%, 145%, 137%, 189%, 130%, respectivley. Compound 16 could increase DiBAC4(3) fluorescence response in both non-specific and specific K+ channel-regulator screening models at the concentration of 1.0 x 10(-5) mol x L(-1). Compound 1 was a new compound and all compounds were isolated from this genus for the first time. Compounds 3,4,6,9,10,14,15,18 and 20 showed neuroprotective activities while 16 exhibited K+ channel-blocking activity.

Ca2+ channel-blocking effect of the yohimbine derivatives, 14 beta-benzoyloxyyohimbine and 14 beta-pho-nitrobenzoyloxyyohimbine.

Yohimbine possesses a relatively selective alpha 2-adrenoceptor antagonistic effect and a weak Ca2+ channel blocking activity, so two derivatives, 14 beta-benzoyloxyyohimbine and 14 beta-rho-nitrobenzoyloxyyohimbine were compared with yohimbine using those parameters. The two derivatives blocked Ca2+-induced contraction of the rat perfused mesenteric vascular bed at 3 X 10(-6) M, and developed dose-dependent shifts of the dose-response curve to the right in concentrations from 3 X 10(-6) to 10(-5) M. Yohimbine showed a weak Ca2+ channel-blocking effect only at a concentration of 10(-5) M. On the other hand, both derivatives at 3 X 10(-6) M did not affect the dose-response curve to noradrenaline-induced vasoconstriction. Furthermore, at 10(-8) M they had no effect on the dose-response curve to clonidine-induced inhibition of the twitch response of the rat isolated vas deferens evoked by electric stimulation, whereas yohimbine significantly attenuated clonidine-induced inhibition. These results indicate that introduction of bulky substituents into the 14-position of yohimbine intensely potentiated the Ca2+ channel-blocking effects and reduced alpha-adrenoceptor antagonistic effects compared with those of yohimbine, and suggest that chemical modifications of yohimbine may lead to structurally new types of Ca2+ channel-blockers.

Synthesis and Calcium Channel Blocking Activity of 1, 4-Dihydropyridine Derivatives Containing Ester Substitute and Phenyl Carbamoyl Group

Problem statement: Several studies on the synthesis of new nifedipine analogs have been carried out, but the literature reveled that no study on the synthesis and calcium channel blocking activity of the substituted ester with an amide (5-phenylcarbamoyl) moiety has been reported. Approach: Six new derivatives of m-nifedipine have been successfully synthesized by substituting an ester moiety with an amide (5-phenylcarbamoyl) moiety, using a modified Hantzsch reactions and tested for their pharmacological activities. The nifedipine analogs 1-6 were characterized and confirmed using elemental analysis, Infrared spectroscopy (IR), Nuclear Magnetic Resonance (1H NMR) and Mass spectroscopy. The purity of the compounds was ascertained by melting point and TLC. The in vitro calcium channel blocking activities were evaluated using the high K+ concentration of Porcine Coronary Artery Smooth Muscles (PCASM) assay. Results: The compounds (1-2) failed to exhibit any blocking activity (IC50 = 10−7 to 10−5 M range), while the compounds 3-6 relaxed precontracted porcine coronary artery smooth muscles with pEC50 values ranging between 4.37±0.10 (compound 3) and 6.46±0.07 (compound 5), indicating that compounds 3-6 exhibit comparable potencies in blocking calcium channels to reference drug varapamil (6.97±0.15) and m-nifedipine (6.48±0.05). Conclusion: The results of this study showed that some of the developed new compounds possess maximal calcium channel blocking effects comparable to m-nifedipine. The developed compounds in the present study will predicatively show an increased metabolic stability and consequently longer duration of actions compared to m-nifedipine and could be, therefore, suitable candidates for further optimization to be evaluated as a new class of antihypertensive drugs.

Synthesis of a New Series of 4-Aryl-1,4-Dihydropyridines with Calcium Channel Blocking and Vasodilatory Activity

Synthesis of a New Series of 4-Aryl-1,4-Dihydropyridines with Calcium Channel Blocking and Vasodilatory Activity

Antibacterial, antifungal, antispasmodic and Ca++ antagonist effects of Caesalpinia bonducella

Caesalpinia bonducella F. (Leguminosae) has been used as a folk medicine for a variety of ailments. The crude extract of C. bonducella and its fractions were studied for antibacterial, antifungal, antispasmodic and Ca++ antagonistic properties. The strongest antibacterial effect was displayed by the n-butanol (72%) and ethyl acetate (80%) fractions, followed by the crude extract (46% and 42%), against Escherichia coli and Bacillus subtilis, respectively. The plant extract and its fractions showed mild to excellent activity in antifungal bioassays, with maximum antifungal activity against Candida glaberata (80%) and Aspergillus flavus (70%) by the n-butanol and chloroform fractions, followed by the crude extract (70% and 65%). Caesalpinia bonducella extract caused concentration-dependent inhibition of spontaneous and high K+ (80 mM)-induced contractions of isolated rabbit jejunum preparations, similar to that caused by Verapamil. These results indicate that C. bonducella exhibits antibacterial, antifungal, spasmolytic and Ca++ channel blocking actions.

Molecular Diversity and Functional Evolution of Scorpion Potassium Channel Toxins

Scorpion toxins affecting K(+) channels (KTxs) represent important pharmacological tools and potential drug candidates. Here, we report molecular characterization of seven new KTxs in the scorpion Mesobuthus eupeus by cDNA cloning combined with biochemical approaches. Comparative modeling supports that all these KTxs share a conserved cysteine-stabilized α-helix/β-sheet structural motif despite the differences in protein sequence and size. We investigated functional diversification of two orthologous α-KTxs (MeuTXKα1 from M. eupeus and BmP01 from Mesobuthus martensii) by comparing their K(+) channel-blocking activities. Pharmacologically, MeuTXKα1 selectively blocked Kv1.3 channel with nanomolar affinity (IC(50), 2.36 ± 0.9 nM), whereas only 35% of Kv1.1 currents were inhibited at 3 μM concentration, showing more than 1271-fold selectivity for Kv1.3 over Kv1.1. This peptide displayed a weak effect on Drosophila Shaker channel and no activity on Kv1.2, Kv1.4, Kv1.5, Kv1.6, and human ether-a-go-go-related gene (hERG) K(+) channels. Although BmB01 and MeuTXKα1 have a similar channel spectrum, their affinity and selectivity for these channels largely varies. In comparison with MeuTXKα1, BmP01 only exhibits a submicromolar affinity (IC(50), 133.72 ± 10.98 nM) for Kv1.3, showing 57-fold less activity than MeuTXKα1. Moreover, it lacks the ability to distinguish between Kv1.1 and Kv1.3. We also found that MeuTXKα1 inhibited the proliferation of activated T cells induced by phorbol myristate acetate and ionomycin at micromolar concentrations. Our results demonstrate that accelerated evolution drives affinity variations of orthologous α-KTxs on Kv channels and indicate that MeuTXKα1 is a promising candidate to develop an immune modulation agent for human autoimmune diseases.

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.

Investigating the Protective Effect of Solanum melongena

The aim of this study is to investigate the protective effect of Solanum melongena (S. Melongena). Different solvent were used to extract the fractions. Antiplatelet activity was monitored using dual channel Lumi aggregometer, antioxidant enzymes were measured using kits purchased from RANDOX, UK while calcium channel blocking activity was screened on guinea pig ileum using isolated organ bath assembly. Aqueous fraction, Ethyl acetate fraction and Chloroform fraction potently inhibited platelet aggregation, antioxidant and calcium channel blocking activity respectively. These results indicated that all fractions of S. Melongena possesses antioxidant properties but aqueous fraction posses both AA and PAF antiplatelet activity and chloroform fraction acts as calcium channel blocker. We hypothesized that fractionation process may be responsible for the modification of the active compounds present in the extracts of S. Melongena and hence for their respective properties. Moreover, PAF aggregation cycle molecules which are involved in blocking may not be soluble either in ethyl acetate or chloroform.

Inhibition of ATP-Sensitive K+ Channels and L-Type Ca2+ Channels by Amiodarone Elicits Contradictory Effect on Insulin Secretion in MIN6 Cells

Some class I antiarrhythmic drugs induce a sporadic hypoglycemia by producing insulin secretion via inhibition of ATP-sensitive K(+) (K(ATP)) channels of pancreatic β-cells. It remains undetermined whether amiodarone produces insulin secretion by inhibiting K(ATP) channels. In this study, effects of amiodarone on K(ATP) channels, L-type Ca(2+) channel, membrane potential, and insulin secretion were examined and compared with those of quinidine in a β-cell line (MIN6). Amiodarone as well as quinidine inhibited the openings of the K(ATP) channel in a concentration-dependent manner without affecting its unitary amplitude in inside-out membrane patches of single MIN6 cells, and the IC(50) values were 0.24 and 4.9 µM, respectively. The L-type Ca(2+) current was also inhibited by amiodarone as well as quinidine in a concentration-dependent manner. Although glibenclamide (0.1 µM) or quinidine (10 µM) significantly potentiated the insulin secretion from MIN6 cells, amiodarone (1-30 µM) failed to increase insulin secretion. Amiodarone (30 µM) and nifedipine (10 µM) significantly inhibited the increase in insulin secretion produced by 0.1 µM glibenclamide. Amiodarone (30 µM) produced a gradual decrease of the membrane potential, but did not produce repetitive electrical activity in MIN6 cells. Glibenclamide (1 µM) produced a slow depolarization, followed by spiking activity which was inhibited by 30 µM amiodarone. Thus, amiodarone is unlikely to produce hypoglycemia in spite of potent inhibitory action on K(ATP) channels in insulin-secreting cells, possibly due to its Ca(2+) channel-blocking action.

Smooth Muscle Relaxant Activity of a Synthetic Dihydropyrimidine Derivative 5-acyl-6-methyl-4(2,3methylenedioxy)phenyl-2-s-benzyl-1,4-dihydro Pyrimidine (bk- vii) on Isolated Rat Uterus and Rabbit Aortic Strip

ObjectivesTo investigate the smooth muscle relaxant activity of a newly synthesised dihydropyrimidine derivative 5-acyl-6-methyl-4(2,3 methylenedioxy) Phenyl-2-S-benzyl-1,4-dihydropyrimidine(code named as BK- VII) and comparing with nifedipine on isolated rat uterus and rabbit aortic strip.Effect of the test compound BK-VII on the smooth muscles of isolated rat uterus and isolated rabbit aortic strip was observed and compared with that of nifedipine. Observations were made with increasing bath concentrations of BK-VII and nifedipine. Six preparations were used for each dose of BK-VII and nifedipine. Mean effect of increasing doses of BK-VII and nifedipine on the height of calcium (Ca²⁺) induced contraction of depolarised isolated rabbit aortic strip and on potassium (K⁺) induced contraction of isolated rat uterus were noted and median inhibitory concentration (IC-50) calculated.ResultsTest compound BK-VII had a significant dose-dependent relaxant effect on K⁺-induced contractions of isolated rat uterus. Significant relaxation was seen at bath concentration starting from 4.2X10⁻⁵M (IC₅₀ -12.2X10⁻⁵M). Nifedipine showed significant relaxation at all bath concentrations starting from 2.8X10⁻⁷M (IC₅₀-7.5X10⁻⁷M). Compound BK-VII produced potentiation of Ca²⁺-induced contractions of K⁺-depolarized rabbit's aortic strip at bath concentration of 0.6X10⁻⁵M while significant inhibition was observed at higher bath concentrations. Nifedipine showed dose-dependent significant inhibition at all bath concentrations.BK-VII has a calcium channel blocking activity like nifedipine and it can inhibit the Ca²⁺ dependent contractions of smooth muscles of uterus and aorta.

Main Cavinton® metabolite cAVA increases neuronal excitability

Event Abstract Back to Event Main Cavinton® metabolite cAVA increases neuronal excitability B. Farkas1*, P. Kocsis1, I. Tarnawa1 and K. Tihanyi1 1 Gedeon Richter Plc.,, Pharmacology and Drug Safety Research, Hungary The sodium channel blocking activity of Cavinton (vinpocetine) is implicated in its anti-excitotoxic actions. Clinical- as well as animal experimental data indicate that vinpocetine has a memory enhancing effect. However, inhibition of sodium channels, which decreases excitability, is difficult to reconcile with a positive effect on memory. Vinpocetine is readily metabolised to cis-apovincaminic acid (cAVA) in rats. We investigated if cAVA could play a role in the memory enhancing effect of vinpocetine, by analysing the effects of cAVA on neuronal excitability in models of cortical spreading depression (CSD) and in spinal reflex experiments. In the rat hemisected spinal cord model, ventral root reflexes recorded from the L5 ventral root following the stimulation of the ipsilateral dorsal root, were dose-dependently enhanced by cAVA (25-400 µM). In brain slices, cAVA (100-200 µM) markedly increased the excitability of cortical tissue. CSDs could have been evoked more easily by application of high-potassium containing medium in the presence of cAVA. In vivo, when CSDs were recorded from the frontoparietal cortex, pre-treatment of rats with cAVA (20 mg/kg; i.v.) elevated the mean amplitude of DC potential shifts without altering the number of CSD events compared to vehicle control. Our findings indicate that cAVA, in contrast with vinpocetine, can directly enhance neuronal excitability. This suggests that the memory enhancing effect of vinpocetine may be due to its bioconversion to cAVA. Keywords: Neurophysiology, Neuroscience Conference: 13th Conference of the Hungarian Neuroscience Society (MITT), Budapest, Hungary, 20 Jan - 22 Jan, 2011. Presentation Type: Abstract Topic: Neurophysiology Citation: Farkas B, Kocsis P, Tarnawa I and Tihanyi K (2011). Main Cavinton® metabolite cAVA increases neuronal excitability. Front. Neurosci. Conference Abstract: 13th Conference of the Hungarian Neuroscience Society (MITT). doi: 10.3389/conf.fnins.2011.84.00115 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 03 Mar 2011; Published Online: 23 Mar 2011. * Correspondence: Dr. B. Farkas, Gedeon Richter Plc.,, Pharmacology and Drug Safety Research, Budapest, Hungary, b.farkas@richter.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers B. Farkas P. Kocsis I. Tarnawa K. Tihanyi Google B. Farkas P. Kocsis I. Tarnawa K. Tihanyi Google Scholar B. Farkas P. Kocsis I. Tarnawa K. Tihanyi PubMed B. Farkas P. Kocsis I. Tarnawa K. Tihanyi Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Functional Characterization and Analgesic Effects of Mixed Cannabinoid Receptor/T-Type Channel Ligands

BackgroundBoth T-type calcium channels and cannabinoid receptors modulate signalling in the primary afferent pain pathway. Here, we investigate the analgesics activities of a series of novel cannabinoid receptor ligands with T-type calcium channel blocking activity.ResultsNovel compounds were characterized in radioligand binding assays and in vitro functional assays at human and rat CB1 and CB2 receptors. The inhibitory effects of these compounds on transient expressed human T-type calcium channels were examined in tsA-201 cells using standard whole-cell voltage clamp techniques, and their analgesic effects in response to various administration routes (intrathecally, intraplantarly, intraperitoneally) assessed in the formalin model. A series of compounds were synthesized and evaluated for channel and receptor activity. Compound NMP-7 acted as non-selective CB1/CB2 agonist while NMP4 was found to be a CB1 partial agonist and CB2 inverse agonist. Furthermore, NMP-144 behaved as a selective CB2 inverse agonist. All of these three compounds completely inhibited peak Cav3.2 currents with IC50 values in the low micromolar range. All compounds mediated analgesic effects in the formalin model, but depending on the route of administration, could differentially affect phase 1 and phase 2 of the formalin response.ConclusionsOur results reveal that a set of novel cannabinioid receptor ligands potently inhibit T-type calcium channels and show analgesic effects in vivo. Our findings suggest possible novel means of mediating pain relief through mixed T-type/cannabinoid receptor ligands.

Effect of Efonidipine on TGF-β1–Induced Cardiac Fibrosis Through Smad2-Dependent Pathway in Rat Cardiac Fibroblasts

Transforming growth factor beta-1 (TGF-β1) plays a critical role in progression of cardiac fibrosis, which may involve intracellular calcium change. We examined effects of efonidipine, a dual T-type and L-type calcium channel blocker (CCB), on TGF-β1-induced fibrotic changes in neonatal rat cardiac fibroblast. T-type and L-type calcium channel mRNAs were highly expressed in cultured cardiac fibroblasts. TGF-β1 (5 ng/mL) significantly increased Smad2 phosphorylation and [(3)H]-leucine incorporation, which were attenuated by pretreatment with efonidipine (10 µM). Neither R(-)efonidipine (10 µM), selective T-type CCB, nor nifedipine (10 µM), selective L-type CCB, efficaciously inhibited both TGF-β1-induced Smad2 phosphorylation and [(3)H]-leucine incorporation. However, both were markedly attenuated by combination of R(-)efonidipine and nifedipine, EDTA, or calcium-free medium. Pretreatment with Smad2 siRNA significantly attenuated [(3)H]-leucine incorporation induced by TGF-β1. These data suggest that efonidipine elicits inhibitory effects on TGF-β1- and Smad2-dependent protein synthesis through both T-type and L-type calcium channel-blocking actions in cardiac fibroblasts.

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.

The electronic structure and dipole moment of charybdotoxin, a scorpion venom peptide with K + channel blocking activity

The electronic structure of charybdotoxin (ChTX), a scorpion venom peptide that is known to act as a potassium channel blocker, is investigated with the aid of semiempirical molecular orbital (MO) calculations. The dipole moment vector ( μ = 145 D at pH = 3.5 and μ = 116 D at pH = 7.5) of ChTX can be steered by the KcsA potassium channel’s macrodipole thereby assuming the proper orientation before the peptide binds the ion channel on the cell surface. The localization of the frontier orbitals of ChTX has been revealed for the first time. HOMO is localized on Trp14 while the three lowest-unoccupied MOs (LUMO, LUMO + 1, and LUMO + 2) are localized on the three disulfide bonds that characterize this peptide. An effective approach to engineer the HOMO–LUMO (H–L) gap of ChTX is replacing its Trp14 residue with Ala14 whereas deletion of the LUMO-associated disulfide bond Cys13-Cys33 through the insertion of a pair of l-α-aminobutyric acid residues does not affect the H–L energy gap. Molecular electrostatic potential surfaces for three ChTX models, two of them charged and one neutral, are in good agreement with the direction of the corresponding electric dipole moments.

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.