Entry Blocking Activity Research Articles

Design, synthesis and cardiovascular evaluation of some aminoisopropanoloxy derivatives of xanthone

A series of aminoisopropanoloxy derivatives of xanthone has been synthesized and their pharmacological properties regarding the cardiovascular system has been evaluated. Radioligand binding and functional studies in isolated organs revealed that title compounds present high affinity and antagonistic potency for α1-(compound 2 and 8), β-(compounds 1, 3, 4, 7), α1/β-(compounds 5 and 6) adrenoceptors. Furthermore, compound 7, the structural analogue of verapamil, possesses calcium entry blocking activity. The title compounds showed hypotensive and antiarrhythmic properties due to their adrenoceptor blocking effect. Moreover, they did not affect QRS and QT intervals, and they did not have proarrhythmic potential at tested doses. In addition they exerted anti-aggregation effect. The results of this study suggest that new compounds with multidirectional activity in cardiovascular system might be found in the group of xanthone derivatives.

Calcium entry blocking activity of the <i>Elaeagnus umbellata</i> fruit extract explains its use in diarrhea and gut spasm

<p class="Abstract">This study was aimed to explore the pharmacological basis of potential medicinal use of <em>Elaeagnus umbellata</em> in gut disorders. Crude extract of <em>E. umbellata</em>, which was found positive for flavonoids, terpenoids and tannins, provided 9.9-71.9% protection in castor oil-induced diarrhea in mice, like verapamil. In isolated rabbit jejunum preparations, crude extract caused inhibition of spontaneous and high K<sup>+</sup>-induced contractions, with respective EC<sub>50</sub> values of 0.3 (0.1-0.5) and 0.5 mg/mL, suggesting Ca<sup>++</sup> channel blockade (CCB). Pretreatment of tissue with crude extract (0.1–1 mg/mL) caused a rightward shift in Ca<sup>++</sup> concentration-response curves. With the exception of aqueous fraction, <em>n</em>-hexane, chloroform and ethyl acetate inhibited spontaneous and high K<sup>+</sup>-induced contractions and displaced rightward Ca<sup>++</sup> concentration-response curves. Extract was found safe up to 10 mg/kg in mice. Our data shows that anti-diarrheal effect of crude extract of <em>E. umbellate</em> is due to CCB-mediated spasmolytic effect, concentrated in the ethyl acetate fraction and suggests its medicinal importance in diarrhea and spasm.</p><p><strong>Video Clip</strong></p><p><a href="https://youtube.com/v/Qo_y3ULC4E0">Isolation of rat jejunum</a>: 2 min 32 sec </p>

Biofunctional studies of new 2-methoxyphenylpiperazine xanthone derivatives with α1-adrenolytic properties

BackgroundThe aim of this study was to assess the selectivity of the studied xanthone derivatives for α1-adrenoceptor subtypes (α1A, α1B, α1D, α1L) in functional experiments in order to verify if they possess any selectivity for a distinct subtype of α1-adrenoceptor. Moreover, several pharmacological tests were carried out to assess whether they reveal other than α1-adrenoceptor blocking properties such as: antagonistic for 5-HT2 receptors, vasorelaxant or spasmolytic. MethodsThe influence on α1A-adrenoceptors was examined in biofunctional studies employing isolated rat vas deferens, on α1B-adrenoceptors in guinea-pig spleen, on α1D-adrenoceptors in rat aorta, and on α1L-adrenoceptors in rabbit spleen. Affinity for 5-HT2 receptors was measured in radioligand binding assay, whereas antagonistic potency for 5-HT2 receptors was studied on isolated rat aorta. Vasorelaxant effect of tested compounds was assessed in functional study employing rat aorta, whereas direct spasmolytic activity was investigated using the isolated rabbit small intestine. ResultsThe present study provides evidences that the tested 2-methoxyphenylpiperazine xanthone derivatives are non-selective α1-adrenoceptor blockers. However, at higher concentrations the direct spasmolytic effect could enhance their hypotensive activity. The obtained results indicate that the studied xanthones possessed weak calcium entry blocking activity, as well as antagonistic properties for 5-HT2A receptors. ConclusionsThe results of the present study support the idea that the hypotensive activity of the studied compounds is related to their α1-adrenolytic properties.

Antiarrhythmic activity of some xanthone derivatives with β1-adrenoceptor affinities in rats

A series of aminoalkanolic derivatives of xanthone with high affinity for β1-adrenoceptors was evaluated for antiarrhythmic activity in the model of ischemia-reperfusion in isolated hearts, as well as in barium chloride- and adrenaline-induced model of arrhythmia. In order to better understand biological activity of studied compounds, the influence on β2-adrenoceptors in guinea-pig trachea and vasorelaxant properties in rat aorta were evaluated. Furthermore, due to assessed antioxidant activity, some biochemical studies were also performed. All tested compounds showed prominent antiarrhythmic activity in the model of ventricular arrhythmias associated with coronary artery occlusion and reperfusion. In this experiment the most active was compound MH-97. Whereas, compound MH-82 was the most active in barium- and adrenaline-induced arrhythmia after i.v. or p.o. administration, respectively. These two compounds have higher affinity to β1-adrenoceptors than compound MH-87, thus it suggests that blocking properties of β1-adrenoceptors are involved in the observed antiarrhythmic effects. All studied compounds have revealed antagonistic potency for β2-adrenoceptors in tracheal smooth muscle, however weaker than that of propranolol. None of tested compounds demonstrated antioxidant effect. They also had weak calcium entry blocking activity. The results of this study suggest that new compounds with antiarrhythmic activity might be found in the group of xanthone derivatives.

Design, synthesis and pharmacological screening of hybrid molecules as antihypertensives

The synthesis and pharmacological profile of a series of hybrid compounds bearing the dihydropyrimidine moiety and substituted phenylthioureas joined via typical β-blocker aryloxypropanolamine group are described. Seven out of 10 new compounds tested proved to be endowed with negative inotropic and chronotropic effect as compared to Adrenaline on isolated perfused frog heart. Also ECG studies that were carried out on normotensive male rats showed that the most of the compounds exhibited significant reduction in Rmax value in the first 30 min although maintaining little change in heart rate, with hypotensive effect lasting for 1 h. We concluded that the most of the synthesized novel compounds exhibited hypotensive as well as antihypertensive effects which could be attributed to blockade of Ca2+ entry and β-adrenoreceptor blocking activities due to introduction of aryloxypropanolamine linked to N-1 substituted dihydropyrimidine moiety. Brady cardiac effects of compounds 5a–5d, 6c–6e resulting from Ca2+ entry and β-adrenoreceptor blocking attenuate the sympathetic activation-associated reflex tachycardia in the heart. We selected compound 5c as a promising lead for further detailed pharmacological and preclinical evaluation studies.

The new generation dihydropyridine type calcium blockers, bearing 4-phenyl oxypropanolamine, display α-/β-Adrenoceptor antagonist and long-Acting antihypertensive activities

A new series of dihydropyridine derivatives, bearing oxypropanolamine moiety on phenyl ring at the 4-position of the dihydropyridine base, were prepared. Oxypropanolamine was synthesized by replacing the phenolic OH of vanillin or other compounds, having a phenyl aldehyde group, with epichlorohydrin, followed by cleavaging the obtained epoxide compounds with tert-butylamine, n-butylamine or 2-methoxy-1-oxyethylamino benzene (guaiacoxyethylamine), respectively. Obtained various oxypropanolamine compounds, still remaining a phenyl aldehyde moiety, were then performed by Hantzsch condensation reaction with methylacetoacetate or ethylacetoacetate, respectively, to give our new series of dihydropyridine linked with the 4-phenyl ring. These compounds were evaluated for inotropic, chronotropic, and aorta contractility that associated with calcium channel and adrenoceptor antagonist activities. Dihydropyridine derivatives that with oxypropanolamine side chain on their 4-phenyl ring associated α-/β-adrenoceptor blocking activities created a new family of calcium entry and the third generation β-adrenoceptor blockers. Optimizing this research to obtain more potent α-/β-adrenoceptor blocking and long-acting antihypertensive oxypropanolamine on the 4-phenyl ring of dihydropyridine series compounds was thus accomplished and classified as third generation dihydropyridine type calcium channel blockers, in comparison with previous short-acting type nifedipine and long-acting type amlodipine. We concluded that compounds 1a, 1b and 1g showed not only markedly high calcium-antagonistic activity but also the highest antihypertensive effect; compounds 1b, 1c, 1f, 1g, 1i and 1j induced sustained antihypertensive effects are major and attributed to their calcium entry and α-adrenoceptor blocking activities in the blood vessel due to their introduction of 2-methoxy, 1-oxyethylamino benzene moiety in the side chain on the 4-phenyl ring of dihydropyridine. Bradycardiac effects of all the compounds 1a– 1j resulted from calcium entry and β-adrenoceptor blocking, which attenuate the sympathetic activation-associated reflex tachycardia in the heart. We selected compound 1b as candidate compound for further pharmacological and pre-clinical evaluation studies.

Third‐generation dihydropyridine‐type calcium channel blocker labedipinedilol‐B displays α/β‐adrenoceptor blocking activities

AbstractThe pharmacological properties of labedipinedilol‐B {N‐[4‐[2‐hydroxy‐3‐(2‐methoxy‐1‐oxyethylaminobenzene) propoxy]‐benzyl]‐2,6‐dimethyl‐3,5‐dicarbomethoxy‐1,4‐dihydropyridine} were investigated in vivo and in vitro in comparison with labedipinedilol‐A. Intravenous labedipinedilol‐B (0.5, 1.0, and 3.0 mg kg–1), produced dose‐dependent hypotensive and bradycardia responses in pentobarbital‐anesthetized Wistar rats. Pretreatment with labedipinedilol‐B (1.0 mg kg–1, iv) also inhibited phenylephrine (10 μg kg–1)‐induced hypertensive and (–)isoproterenol (0.5 μg kg–1)‐induced tachycardia effects. In the isolated Wistar rat right and left atria and guinea pigs tracheal strips experiments, labedipinedilol‐B (10–7, 10–6, and 10–5 M) competitively antagonized the (–)isoproterenol‐induced positive chronotropic and inotropic effects and tracheal relaxation responses in a concentration‐dependent manner. The parallel shift to the right of the concentration–response curve of (–)isoproterenol suggested that labedipinedilol‐B was a β1/β2‐adrenoceptor competitive antagonist. Labedipinedilol‐B (10–7, 10–6, and 10–5 M) also prevented the rate‐increasing effects of increased extracellular Ca2+ (3.0–9.0 mM) in a concentration‐dependent manner. In the isolated rat aorta, labedipinedilol‐B (10–7, 10–6, and 10–5 M) competitively antagonized the CaCl2 and norepinephrine‐induced contractions with pKCa–1 and pA2 values of 8.02 ± 0.04 and 7.55 ± 0.05 in a concentration‐dependent manner. The parallel shift to the right of the concentration–response curves of norepinephrine suggested that labedipinedilol‐B was an α‐adrenoceptor competitive antagonist. Furthermore, labedipinedilol‐B, in an equal antagonist activity, inhibited norepinephrine‐induced phasic and tonic contraction. In the isolated rat aorta, labedipinedilol‐B also competitively antagonized CaCl2‐induced contractions and made the parallel shift to the right of the concentration–response curve of CaCl2. In cultured blood vessel smooth muscle cells (A7r5 cell lines), Bay K 8644‐induced intracellular calcium changes were decreased after application of labedipinedilol‐B, suggesting that the compound was a calcium channel blocker. The binding characteristics of labedipinedilol‐B were evaluated in [3H]CGP‐12177 binding to ventricle and lung and [3H]prazosin binding to brain membranes in rats. Labedipinedilol‐B also was evaluated in [3H]nitrendipine binding to brain membranes in rats. These results indicated that labedipinedilol‐B, similar to labedipinedilol‐A, has α‐adrenoceptor blocking, β‐adrenoceptor blocking, and calcium entry blocking activities in a single compound. We suggest that these two compounds represent a new generation of 1,4‐dihydropyridine‐type calcium channel blockers. Drug Dev. Res. 52:462–474, 2001. © 2001 Wiley‐Liss, Inc.

Labedipinedilol-A: A vanilloid-based ?/?-adrenoceptor blocker with calcium entry blocking and long-acting antihypertensive properties

The combination of β-adrenoceptor blockade and vasodilator action have proved highly useful in antihypertensive therapy. Studies of the mechanisms of action of labedipinedilol-A that combine these effects within a single molecule are described in this report. Intravenous labedipinedilol-A (0.1–1.0 mg/kg) produced dose-dependent hypotensive and bradycardia responses for above 1.0 h, significantly different from nifedipine (0.5 mg/kg, i.v.)-induced hypotensive and reflex tachycardia activities in pentobarbital-anesthetized Wistar rats. Pretreatment with labedipinedilol-A also inhibited phenylephrine (20 μg/kg, i.v.)-induced hypertensive and (-)isoprenaline (0.5 μg/kg, i.v.)-induced tachycardia effects. Oral administration of labedipinedilol-A (5–50 mg/kg) in spontaneously hypertensive rats (SHR) reduced the blood pressure and heart rate for 24 h but did not increase heart rate. Labedipinedilol-A (10–7–10–5 M) competitively antagonized (-)isoprenaline (10–10–10–4M)-induced positive chronotropic and inotropic effects of the isolated rat atria and tracheal relaxation responses of the isolated guinea pig tissues. Labedipinedilol-A also prevented the rate-increasing effects of increased extracellular Ca2+ (3.0–9.0 mM) in a concentration-dependent manner. In the isolated rat aorta, labedipinedilol-A competitively antagonized CaCl2 and norepinephrine-induced contractions with pKCa–1 and pA2 values of 8.46 ± 0.05 and 8.28 ± 0.03 and had a potent effect of inhibiting high K+-induced vasocontraction. Furthermore, labedipinedilol-A, in an equal antagonist activity, inhibited norepinephrine-induced phasic and tonic contraction. In the cultured blood vessel smooth muscle cell (A7r5 cell line), KCl, norepinephrine, and Bay K 8644-induced intracellular calcium changes were decreased after application of labedipinedilol-A (10–9–10–6 M). The binding characteristics of labedipinedilol-A were evaluated in [3H]CGP-12177 binding to ventricle and lung and [3H]nitrendipine and [3H]prazosin binding to brain membranes in rats. The -logIC50 values of labedipinedilol-A for β1-, β2-, and α1-adrenoceptor and calcium channel, were 8.17 × 10–7 M, 8.20 × 10–7 M, 2.20 × 10–8 M, and 2.46 × 10–8 M, respectively. Labedipinedilol-A-induced sustained depressor effect was mainly attributed to its calcium entry and α-adrenoceptor blocking activities in the blood vessel. Sustained bradycardia effect resulted from β-adrenoceptor and calcium entry blocking, which deleted the sympathetic activation-associated reflex tachycardia in the heart. Drug Dev. Res. 49:94–108, 2000. © 2000 Wiley-Liss, Inc.

Vanidipinedilol: a vanilloid-based beta-adrenoceptor blocker displaying calcium entry blocking and vasorelaxant activities.

Calcium channel and beta-adrenoceptor blockade have proved highly useful in antihypertensive therapy. Studies of the mechanisms of action of vanidipinedilol that combine these effects within a single molecule are described here. Intravenous injection of vanidipinedilol (0.1, 0.25, 0.5, 1.0, and 2.0 mg/kg) produced dose-dependent hypotensive and bradycardic responses, significantly different from nifedipine-induced (0.5 mg/kg, i.v.) hypotensive and reflex tachycardic effects in pentobarbital-anesthetized Wistar rats. A single oral administration of vanidipinedilol at doses of 10, 25, and 50 mg/kg dose-dependently reduced blood pressure with a decrease in heart rate in conscious spontaneously hypertensive rats (SHRs). In the isolated Wistar rat atrium, vanidipinedilol (10(-7), 10(-6), and 10(-5) M) competitively antagonized the (-)isoproterenol-induced positive chronotropic and inotropic effects and inhibited the increase in heart rate induced by Ca2+ (3.0-9.0 mM) in a concentration-dependent manner. The parallel shift to the right of the concentration-response curve of (-)isoproterenol and CaCl2 suggested that vanidipinedilol possessed beta-adrenoceptor-blocking and calcium entry-blocking activities. On tracheal strips of reserpinized guinea pig, cumulative doses of vanidipinedilol (10(-10) to 3x10(-6) M) produced dose-dependent relaxant responses. Preincubating the preparation with ICI 118,551 (10(-10), 10(-9), 10(-8) M), a beta2-adrenoceptor antagonist, shifted the vanidipinedilol concentration-relaxation curve significantly to a region of higher concentrations. These results implied that vanidipinedilol had a partial beta2-agonist activity. In the isolated thoracic aorta of rat, vanidipinedilol had a potent effect inhibiting high-K+-induced contractions. KCI-induced intracellular calcium changes of blood vessel smooth muscle cell (A7r5 cell lines) determined by laser cytometry also was decreased after administration of vanidipinedilol (10(-8), 10(-7), 10(-6) M). Furthermore, the binding characteristics of vanidipinedilol and various antagonists were evaluated in [3H]CGP-12177 binding to ventricle and lung and [3H]nitrendipine binding to cerebral cortex membranes in rats. The order of potency of beta1- and beta2-adrenoceptor antagonist activity against [3H]CGP-12177 binding was (-)propranolol (pKi, 8.59 for beta1 and 8.09 for beta2) > vanidipinedilol (pKi, 7.09 for beta1 and 6.64 for beta2) > atenolol (pKi, 6.58 for beta1 and 5.12 for beta2). The order of potency of calcium channel antagonist activity against [3H]nitrendipine binding was nifedipine (pKi, 9.36) > vanidipinedilol (pKi, 8.07). The ratio of beta1-adrenergic-blocking/calcium entry-blocking selectivity is 0.1 and indicated that vanidipinedilol revealed more in calcium entry-blocking than in beta-adrenergic-blocking activities. It has been suggested that vanidipinedilol-induced smooth muscle relaxation may involve decreased entry of Ca2+ and partial beta2-agonist activities. In conclusion, vanidipinedilol is a nonselective beta-adrenoceptor antagonist with calcium channel blocking and partial beta2-agonist associated vasorelaxant and tracheal relaxant activities. Particularly, the vasodilator effects of vanidipinedilol are attributed to a synergism of its calcium entry blocking and partial beta2-agonist activities in the blood vessel. A sustained bradycardic effect results from beta-adrenoceptor blocking and calcium entry blocking, which blunts the sympathetic activation-associated reflex tachycardia in the heart.

Lercanidipine: a novel lipophilic dihydropyridine calcium antagonist with long duration of action and high vascular selectivity

Lercanidipine is a new 1,4-dihydropyridine derivative with potent, long-lasting and vascular-selective calcium entry blocking activity. Animal models of hypertension have shown lercanidipine to be potent, with a slow rate of onset and long lasting action and to have minimal or no effects on cardiac contractility. There was no evidence of tolerance after repeated oral treatment, and no effects were found on the autonomic nervous, central nervous, gastrointestinal or respiratory systems at antihypertensive doses. In man, lercanidipine is well absorbed after oral administration, with peak plasma levels occurring approximately 1.5 - 3 h after dosing. The drug is subject to extensive hepatic first pass metabolism with an elimination half-life of 2 - 5 h. With a more sensitive method, a mean terminal elimination half-life of 8 - 10 h was defined. Despite this short plasma half-life the drug has a long duration of action, most likely due to the high lipophilicity of lercanidipine and its partitioning in to the lipid bilayer of cell membranes, followed by diffusion to the receptor binding site. The efficacy of lercanidipine has been established in extensive clinical trials with comparison to both placebo and standard well-established antihypertensive therapies. These trials confirmed the efficacy of lercanidipine and its long duration of action which renders it suitable for once daily administration. Tolerability was good in all studies: the adverse event profile was comparable to that of placebo at lower doses, with a low incidence of palpitations and ankle oedema. Lercanidipine is a recently introduced example of a lipophilic and vasoselective dihydropyridine calcium antagonist which is an effective antihypertensive drug with a slow onset and long duration of action; it is associated neither with reflex tachycardia nor cardio-depressant activity.

Ferulidilol: A vasodilatory and antioxidant adrenoceptor and calcium entry blocker, with ancillary ?2-agonist activity

Intravenous injection of ferulidilol (0.5, 1.0, 1.5 mg kg−1) produced dose-dependent hypotensive and bradycardia responses in pentobarbital-anesthetized Wistar rats. Ferulidilol competitively antagonized (-)isoprenaline-induced positive inotropic and chronotropic effects of the atria and tracheal relaxation responses on isolated guinea pig tissues. The parallel shift to the right of the concentration–response curve of (-)isoprenaline suggested that ferulidilol was a β-adrenoceptor antagonist. The apparent pA2 values were 8.04 ± 0.09 for the right atria, 8.03 ± 0.15 for the left atria, and 7.51 ± 0.06 for the trachea, respectively. Ferulidilol was more potent than labetalol. In thoracic aorta experiments, ferulidilol also produced a competitive antagonism of norepinephrine- and CaCl2-induced contraction with pA2 and pKCa−1 values of 7.05 ± 0.03 and 6.04 ± 0.05, respectively. Ferulidilol produced cumulative relaxation responses on isolated tracheal strips from reserpine-treated guinea pigs. The effects were competitively antagonized by ICI 118,551 (10−8–10−6 M), a relatively selective β2-adrenoceptor antagonist. The results implied that ferulidilol had partial β2-agonist activity. In the radioligand binding assay, ferulidilol produced dose-dependent inhibition of [3H]CGP-12177 binding to rat ventricle and lung membranes with Ki values of 3.40 and 17.94 nM, respectively. In addition, ferulidilol also antagonized [3H]prazosin and [3H]nitrendipine binding to rat brain membrane with Ki values of 32.48 and 305.01 nM, respectively. These results further confirmed the α/β and calcium entry blocking activities of ferulidilol described in functional studies. Furthermore, ferulidilol (10−8–10−5 M] inhibited lipid peroxidation induced by Fe2+ and ascorbic acid, indicating that it possesses the antioxidant activity inherent in ferulic acid. Our results demonstrate that ferulidilol is a new generation α/β-adrenoceptor blocker with ancillary calcium entry blockade, partial β2-agonist activities and additional antioxidant effects. Drug Dev. Res. 47:77–89, 1999. © 1999 Wiley-Liss, Inc.

Hypotensive effects of YM430, a 1,4-dihydropyridine derivative, in spontaneously hypertensive rats and renal hypertensive dogs.

The hypotensive effects of YM430 (4(((S)-2-hydroxy-3-phenoxypropyl)amino)butyl methyl 2,6-dimethyl-((S)-4-(m-nitrophenyl))-1,4-dihydropyridine-3,5-dicarboxyla te) were evaluated in hypertensive animals. In conscious spontaneously hypertensive rats (SHR), single oral administration of YM430 (10-100 mg/kg) produced a dose-dependent decrease in mean blood pressure (MBP) with slight reflex tachycardia. The hypotensive effect of YM430 reached its maximum about 2 hr after dosing and lasted for over 10 hr. Importantly, the beta 1-adrenoceptor blocking activity of YM430 had a similar time course to that of its calcium entry blocking activity. In conscious normotensive dogs (NTD: 1-10 mg/kg, p.o.), YM430 decreased MBP without reflex tachycardia, and inhibited isoproterenol (ISO)-induced tachycardia in a dose-dependent manner. In conscious renal hypertensive dogs (RHD: 0.3-3 mg/kg, p.o.), YM430 also produced a sustained hypotensive effect. Furthermore, on repeated oral administration to conscious SHR and NTD, YM430 caused a long-lasting hypotensive effect. This hypotensive activity and inhibition of ISO-induced tachycardia showed neither tolerance, augmentation nor rebound. In conclusion, YM430 has a long-lasting hypotensive effect and behaves as a hybrid compound, combining calcium entry blocking and beta 1-adrenoceptor blocking activities in vivo. In addition, the degree of the blocking activities of YM430 remains nearly constant in the long-term after oral administration.

Hypotensive Effects of YM430, a 1,4-Dihydropyridine Derivative, in Spontaneously Hypertensive Rats and Renal Hypertensive Dogs

The hypotensive effects of YM430 (4(((S)-2-hydroxy-3-phenoxypropyl)amino)butyl methyl 2,6-dimethyl-((S)-4-(m-nitrophenyl))-l,4-dihydropyridine-3,5-dicarboxylate) were evaluated in hypertensive animals. In conscious spontaneously hypertensive rats (SHR), single oral administration of YM430 (10-100 mg/kg) produced a dose-dependent decrease in mean blood pressure (MBP) with slight reflex tachycardia. The hypotensive effect of YM430 reached its maximum about 2 hr after dosing and lasted for over 10 hr. Importantly, the β1-adrenoceptor blocking activity of YM430 had a similar time course to that of its calcium entry blocking activity. In conscious normotensive dogs (NTD: 1-10mg/kg, p.o.), YM430 decreased MBP without reflex tachycardia, and inhibited isoproterenol (ISO)-induced tachycardia in a dose-dependent manner. In conscious renal hypertensive dogs (RHD: 0.3-3 mg/kg, p.o.), YM430 also produced a sustained hypotensive effect. Furthermore, on repeated oral administration to conscious SHR and NTD, YM430 caused a long-lasting hypotensive effect. This hypotensive activity and inhibition of ISO-induced tachycardia showed neither tolerance, augmentation nor rebound. In conclusion, YM430 has a long-lasting hypotensive effect and behaves as a hybrid compound, combining calcium entry blocking and β1-adrenoceptor blocking activities in vivo. In addition, the degree of the blocking activities of YM430 remains nearly constant in the long-term after oral administration.

Role of mevalonate in smooth muscle cell proliferation

It has long been discussed why dihydropyridine calcium antagonists are less cardioactive than other calcium antagonists at doses equally effective on vascular smooth muscle [5, 12]. Recently, it has been reported that dihydropyridine calcium antagonists, unlike other calcium antagonists, inhibit adenosine 3′,5′-cyclic monophosphate phosphodiesterase in various tissue preparations [2, 8, 10]. It has also been reported that intracellularly applied adenosine 3′,5′-cyclic monophosphate increases the slow inward current in heart cells [1, 11, 13]. Therefore, present experiments were carried out to elucidate the effects of intracellularly applied calcium antagonists on the slow inward current of single ventricular cells with the patchclamp, ‘whole-cell recording’, technique [3]. Nifedipine, nicardipine and isobutylmethylxanthine, when applied intracellularly using the patch-clamp microelectrode, increased the plateau and the duration of action potentials of single ventricular heart cells of the guinea-pig. The augmentation of the action potential was abolished by superfusing the cell with nifedipine. D600 and diltiazem when applied either intra- or extra-cellularly decreased the plateau and the duration of the action potential. Under voltage clamp conditions, intracellularly applied nifedipine, nicardipine and isobutylmethylxanthine increased the slow inward current, whereas D600 and diltiazem decreased the current. The holding current and the current at the end of 200-ms clamp pulses were not modified. Thus, dihydropyridine calcium antagonists probably increase the slow inward current from the inside of the cell and attenuate the calcium entry blocking activities in heart cells. This must partly be a reason why dihydropyridine calcium antagonists are less cardioactive than D600 and diltiazem at doses equally effective on vascular smooth muscle.

Antianginal effects of YM-16151-4 in various experimental angina models.

The antianginal effects of YM-16151-4, a combined calcium entry blocking and beta 1-adrenoceptor blocking agent, were evaluated in various experimental angina models and compared with those of nifedipine and propranolol. In anesthetized dogs, YM-16151-4 (0.3 and 1 mg/kg intravenously, i.v.) increased coronary blood flow and reduced myocardial oxygen consumption (MVO2). In isolated dog coronary arteries, YM-16151-4 concentration-dependently inhibited 3,4-diaminopyridine-induced rhythmic contractions with an IC50 value of 91 nM. In anesthetized rats, YM-16151-4 also inhibited the ST-segment depression induced by vasopressin (0.5 U/kg i.v.) with an ED50 value of 29 mg/kg orally, (p.o.). Nifedipine was also effective in these models, but propranolol was not. In addition, YM-16151-4 (0.3 mg/kg i.v.) inhibited the ST-segment elevation in the epicardial ECG induced by coronary artery occlusion in anesthetized dogs. Propranolol (1 mg/kg i.v.) also inhibited this elevation, but nifedipine (0.003 mg/kg i.v.) did not. In anesthetized dogs, furthermore, the prolongation of PQ-interval induced by YM-16151-4 was almost the same as that induced by propranolol. These results demonstrate that YM-16151-4, in contrast to nifedipine and propranolol, is fully effective in these various types of angina models. Thus, YM-16151-4 is expected to prove a valuable antianginal agent in treatment of various types of angina pectoris, with these antianginal effects resulting from the sum of its calcium entry blocking and beta 1-adrenoceptor blocking activities.

Calcium entry blocking activities of MPC-1304 and of its enantiomers and metabolites

The Ca 2+ entry blocking effects of MPC-1304, a new Ca 2+ entry blocker of the 1,4-dihydropyridine type, and of its (S) and (R) enantiomers and metabolites were examined on Ca 2+-induced contractions in isolated rabbit arteries. The Ca 2+ entry blocking activity of the (S) enantiomer of MPC-1304 was approximately 150 times greater that that of its (R) enantiomer. Likewise, the antihypertensive effect of the (S) enantiomer was twice as great as that of MPC-1304 (racemate) in conscious spontaneously hypertensive rats, while the (R) enantiomer was ineffective. Thus, most of the pharmacological activity of MPC-1304 resides in its (S) configuration. The main metabolic products of MPC-1304 lso inhibited the Ca 2+-induced contraction in the isolated vascular smooth muscles. These active metabolites showed a stereoselectivity similar to that of MPC-1304 for Ca 2+ entry blocking activity, and may contribute to the potent antihypertensive action of MPC-1304.

ChemInform Abstract: New Prenylamine Analogues: Synthesis and Ca2+‐Entry Blocking Activity.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

New prenylamine analogues: synthesis and Ca 2+-entry blocking activity

The synthesis of a series of diphenylalkylamine derivatives related to prenylamine is reported. The amphetamine group in the prenylamine structure was replaced by other moieties. In addition to substitutions in the aromatic rings, heteroatoms such as sulphur and oxygen were introduced in the chain. The calcium-entry blocking activity was assayed in binding experiments on a guinea-pig brain membrane preparation by displacing [ 3H]-nitrendipine.

Effects of praeruptorin C and E isolated from ‘Qian-Hu’ on swine coronary artery and guinea-pig atria

Praeruptorin C and E isolated from Peucedanum praeruptorum Dunn. decreased the maximum contractile effect of Ca 2+ in potassium-depolarized swine coronary strips and shifted the concentration-response curve to the right in a non-parallel manner. The calcium antagonistic activity of praeruptorin C and E expressed as pD 2 ′ value was 5.7 and 5.2, respectively. Nifedipine, with a pD 2 ′ value of 6.88, was used as a known calcium antagonistic drug to compare the potency of the drugs studied. The relaxation induced by praeruptorin C was concentration-dependent and the IC 50 value was 79 μM. Praeruptorin C also reduced the maximum contractile response and shifted the concentration-response curve for calcium to the right in a non-parallel manner in potassium-depolarized guinea-pig left atria (pD 2 ′ = 5.52) but its potency was much less than that of nifedipine (pD 2 ′ = 7.19). The results suggest that praeruptorin C and E relaxed swine coronary artery and decreased contractility in guinea-pig left atria. These affects are similar in many respects to those displayed by drugs that have calcium entry blocking activity.

Relaxing effects of dilazep and lidoflazine in dog cerebral and renal arteries independent of adenosine.

The adenosine potentiating drugs dilazep and lidoflazine were studied for their relaxing ability in isolated dog cerebral and renal arteries contracted under conditions which induce the opening of potential-dependent calcium channels (using K+ at 30, 50 and 100 mmol/l) and under conditions which induce the opening of receptor-operated calcium channels (prostaglandin F2 alpha, PGF2 alpha; 5-hydroxytryptamine, 5-HT) and compared with those of adenosine and a standard calcium entry blocker, diltiazem. Dilazep, lidoflazine and diltiazem exerted concentration-dependent relaxation in cerebral and renal artery ring strips contracted with 30, 50 and 100 mmol/l K+. However, dilazep was slightly more potent at 100 mmol/l K+. In contrast, whereas the high concentration of adenosine (1 X 10(-5)-3.7 X 10(-4) mol/l) relaxes these arteries only at 30 mmol/l K+, it produced a more pronounced concentration-dependent relaxation when PGF2 alpha or 5-HT was used as a contracting agent. The order of relaxing responses of both cerebral and renal arterial ring strips contracted by PGF2 alpha were: diltiazem greater than adenosine greater than lidoflazine greater than dilazep. On the other hand, the relaxing responses on cerebral and renal arteries contracted with 5-HT were: diltiazem greater than lidoflazine greater than adenosine greater than dilazep and diltiazem greater than adenosine greater than lidoflazine greater than dilazep, respectively. Adenosine deaminase reversed the relaxation produced by adenosine, but was unable to reverse the relaxing responses to diltiazem, lidoflazine and dilazep. These findings suggest that dilazep and lidoflazine have a direct relaxing effect independent of adenosine in cerebral and renal artery ring strips possibly through their calcium entry blocking activity. The data suggest that adenosine is more effective on the receptor-operated contractions, whereas dilazep and lidoflazine are more effective on the potential-dependent contractions.