Α-blocking Activity Research Articles

Synthesis and molecular docking of some new bis-thiadiazoles as anti-hypertensive α-blocking agents

Twelve bis-thiadiazole derivatives were synthesized in high yield via the reaction of 2,2′-terephthaloyl bis(N-phenylhydrazine carbothioamide) with a variety of hydrazonoyl chlorides in ethanol containing catalytic amounts of TEA. All the newly synthesized compounds were characterized by physical and chemical tools (FT-IR, 1H NMR, 13C NMR, and Mass spectrometry). Moreover, all the novel synthesized derivatives were screened for their antihypertensive α-blocking efficacy against to assess their pharmaceutical significance. The encouraging promising results obtained from antihypertensive α-blocking activity studies on the newly synthesized derivatives make the synthesis of a new series of these compounds and studying of their pharmaceutical importance an active area for more and more investigations. The molecular docking of the most active derivative 15 b against the human dopamine D3 receptor was performed by the Molecular Operating Environment (MOE 2014. 0901) program.

Antihypertensive drugs

Antihypertensive drugs

Synthesis and Antihypertensive α-Blocking Activity Evaluation of Thiazole Derivatives Bearing Pyrazole Moiety

Synthesis and Antihypertensive α-Blocking Activity Evaluation of Thiazole Derivatives Bearing Pyrazole Moiety

Alpha blockade potentiates CPVT therapy in calsequestrin-mutant mice.

Spontaneous calcium release evoking delayed afterdepolarization is believed to cause catecholaminergic polymorphic ventricular tachycardia (CPVT), a lethal human arrhythmia provoked by exercise or emotional stress. β-Adrenergic blockers are the drug of choice, but fail to achieve complete arrhythmia control in some patients. These individuals often require flecainide, device implantation, and/or sympathetic denervation. To optimize the arrhythmia therapy by pharmacological inhibition of the sympathetic nervous system in the homozygous calsequestrin knockout (CASQ2(Δ/Δ)) mouse model of CPVT2. A heart telemetry device was implanted for continuous electrocardiographic recording at rest and during provocation testing. Calcium transients and abnormal calcium release were studied in cardiomyocytes isolated from adult mice. Adrenergic receptor expression was determined by using Western blotting and confocal microscopy. Adult CASQ2(Δ/Δ) mice suffer from complex ventricular arrhythmia at rest and ventricular tachycardia during treadmill exercise and after epinephrine injection. β-Adrenergic blockers, propranolol and metoprolol, attenuated arrhythmia at rest but not after stress. Reserpine had no efficacy in controlling arrhythmia. Agents with α-blocking activity, phentolamine or labetalol, abolished both exercise- and epinephrine-induced arrhythmia. In contrast, injection of α-adrenergic agonist phenylephrine reproducibly provoked ventricular tachycardia. Isolated cardiomyocytes from CASQ2(Δ/Δ) mice had delayed calcium release waves upon exposure to sympathetic agonists, which were abolished by phentolamine. Hearts of calsequestrin-mutant mice expressed more α1-adrenergic receptor than did wild type control mice (P < .05). We identified a contribution of the α-adrenergic pathway to the pathogenesis of catecholamine-induced arrhythmia. α-Blockade emerges as an effective therapy in the murine model of CPVT2 and should be tried in humans resistant to β-blockers.

Novel 4-substituted-2(1H)-phthalazinone derivatives: synthesis, molecular modeling study and their effects on α-receptors

Novel 4-(4-bromophenyl)phthalazine derivatives connected via an alkyl spacer to amine or N-substituted piperazine were designed and synthesized as promising α-adrenoceptor antagonists. The structures of the phthalazine derivatives were established using elemental and spectral analyses. Twelve of the tested compounds displayed significant α-blocking activity. Molecular modeling studies were performed to rationalize the biological results. Among the tested compounds, 7j displayed the best-fitting score and the highest in vitro activity.

In vitro and in vivo alpha-blocking activity of thymoxamine and its two metabolites.

The alpha-adrenoceptor potency of thymoxamine and its two metabolites deacetylthymoxamine and demethyldeacetylthymoxamine were determined on the contraction of rat vas deferens induced by noradrenaline, the blood pressure increase induced by noradrenaline given i.v. to dogs and the contraction of the nictitating membrane induced by electrical stimulation in cats. In vivo the three drugs were administered at 6.35 x 10(-6) mol kg-1 intravenously. Deacetylthymoxamine presented nearly the same alpha-blocking activity as the parent drug. This was ascribed in vivo to the rapid deacetylation of thymoxamine. Demethyldeacetylthymoxamine was less active. In vitro its pA2 was 6.20 +/- 0.09 compared with 6.75 +/- 0.20 for thymoxamine and 6.57 +/- 0.13 for deacetylthymoxamine. In vivo, it was inactive in dog and less active than the other two drugs soon after its administration in the cat. The oral LD 50 values in the mouse for the three drugs were respectively 0.81, 0.71 and 1.14 mmol kg-1 for thymoxamine, deacetylthymoxamine and demethyldeacetylthymoxamine.

Influence of gestational diabetes mellitus on the stereoselective kinetic disposition and metabolism of labetalol in hypertensive patients

This study investigated the influence of gestational diabetes mellitus on the kinetic disposition and stereoselective metabolism of labetalol administered intravenously or orally. Thirty hypertensive women during the last trimester of pregnancy were divided into four groups: non-diabetic and diabetic women treated with intravenous or oral labetalol. The pharmacokinetics of labetalol was not stereoselective in diabetic or non-diabetic pregnant women receiving the drug intravenously. However, oral administration of labetalol resulted in lower values of the area under the plasma concentration versus time curve (AUC) for the β-blocker (RR) than for the other enantiomers in both diabetic and non-diabetic women. Gestational diabetes mellitus caused changes in the kinetic disposition of the labetalol stereoisomers when administered orally. The AUC values for the less potent adrenoceptor antagonist (SS) and for the α-blocking (SR) isomers were higher in diabetic than in non-diabetic pregnant women. The approximately 100% higher AUC values obtained for the (SR) isomer in diabetic pregnant women treated with oral labetalol may be of clinical relevance in terms of the α-blocking activity of this isomer.

Synthesis and reactions of thiosemicarbazides, triazoles, and Schiff bases as antihypertensive α-blocking agents

Methyl 2-(thiazol-2-ylcarbamoyl)acetate was synthesized and used as starting material. It was treated with hydrazine hydrate to afford the hydrazide, which was reacted with nitromethane and formaldehyde to give the saturated nitropyrimidine. The hydrazide was reacted with phenyl isothiocyanate to afford the thiosemicarbazide, which was cyclized with ethyl bromoacetate, sodium hydroxide, or sulfuric acid to afford N-phenylthiazolidinone, N-phenyltriazole, and thiadiazolyl derivatives. The methyl 2-(thiazol-2-ylcarbamoyl)acetate was coupled with diazonium salts of aniline, 4-chloroaniline, 4-bromoaniline, or 4-aminobenzenesulfonamide to afford the carbamoyl acetates, which were reacted with 2-aminobenzimidazole, 1,2,4,5-tetrachlorophthalic anhydride, and hydrazine hydrate to afford the corresponding thiazolylmalonamide, tetrachloroisoindolylimide, and tri-azole derivatives. Schiff bases and imides are newly synthesized candidates obtained via simple condensation of the hydrazide with aldehydes, 2,3-pyridinedicarboxylic anhydride, or 1,8-naphthalenedicarboxylic anhydride. The pharmacological screening showed that many of these compounds have good antihypertensive α-blocking activity and low toxicity.

Use of dextran-primed extracorporeal circuit in the canine model for venous return: with special references to the effects of two dihydropyridine-type Ca 2+ channel blockers

1. 1. A successful canine “venous return (VR)” model is described, in which all hemodynamic parameters were stable for about an hour, by minimizing extracorporeal circuit primed with dextran (DX) so that the dilution of the blood was kept about 33%. 2. 2. Increases in VR by norepinephrine (1 μg/kg) and dose-dependent decreases in VR by glyceryl trinitrate (1–30 μg/kg) were clearly observed. 3. 3. While 1 μg/kg of nifedipine produced a small, but significant decrease in VR, only a tendency for decrease was observed with higher doses which produced a definite fall in blood pressure. 4. 4. Nisoldipine (1 μg/kg) caused a small decrease in VR. However, higher doses that produced a large and persistent hypotension produced an increase in VR due probably to intense reflex translocation of the blood. The increase in VR was reversed with carvedilol, a β-blocker with α-blocking activity.

New pyridazinones: synthesis and correlation between structure and α-blocking activity

The synthesis of a series of 5-(4-piperazinyl)-3(2 H)-pyridazinone has been reported. The blocking activity of these compounds was determined on the pre- and postsynaptic α-adrenoreceptors of isolated rat vas deferens.

Effect of Carvedilol on Venous Return: A Mechanism of Reduction in Blood Pressure

We studied the effect of carvediloi, a β-blocker with a potent α-blocking activity, on venous return in anesthetized dogs. Though 3 μg/kg of carvediloi caused a slight increase in blood pressure and total peripheral resistance, these changes disappeared by further doses of the agent. On the other hand, each dose of carvediloi (3-100 μg/kg) decreased venous return significantly and dose-dependently. These results indicate that the hypotensive effect of carvediloi mainly depends on the decrease in venous return rather than arterial vasodilation.

Novel phenoxyalkylamine derivatives. I. Synthesis and pharmacological activities of alpha-isopropyl-alpha-[(phenoxyalkylamino)alkyl]benzeneaceton itrile derivatives.

Novel α-isopropyl-α-[(phenoxyalkylamino)alkyl]benzeneacetonitrile derivatives, the phenoxyalkylamino moiety of which was introduced in place of the phenethylamino moiety of verapamil (known to be an excellent Ca2+-antagonist), were synthesized and their pharmacological activities were evaluated. These compounds exhibited α-bloking activity along with Ca2+-antagonistic activity, and their activities were influenced by the substituent on the amino nitrogen atom and by the number of carbons between the nitrogen atom and the benzeneacetonitrile moiety (m) as well as that between it and the pheoxy moiety (n). Among these compounds, the N-methyl derivative (2h) where m=n=3, was found to possess a high Ca2+-antagonistic activity and the N-H derivative (2c) in which m=3 and n=2 possessed a high α-blocking activity.

Synthesis and α-blocking activity of some analogues of idazoxan

Several analogues of idazoxan 1 and fenmetazole 2 were prepared as potential α 2-adrenoreceptor antagonists. Their blocking activity and selectivity on α 1- and α 2-adrenoreceptors were evaluated in isolated rat vas deferens. Although all the drugs displayed a significantly lower activity compared to the parent compounds 1 and 2, with 3 being the only exception, the present results might help in elucidating the role of ring oxygens of 1 in drug—receptor interaction.

Mechanisms of the Acute Hypotensive Effect of β-Adrenergic Blocking Drugs with α-Blocking Activity in Conscious SHR

Mechanisms of the Acute Hypotensive Effect of β-Adrenergic Blocking Drugs with α-Blocking Activity in Conscious SHR

本態性高血圧症の循環動態に及ぼすα，βしゃ断剤Ａｒｏｔｉｎｏｌｏｌ（Ｓ‐５９６），αしゃ断剤Ｂｕｎａｚｏｓｉｎ（Ｅ‐６４３）およびＰｒａｚｏｓｉｎの効果の比較

Hemodynamic studies using radiocardiocardiography with radioactive iodinated human serum albumin [RIHSA] were performed in thirty-four patients with essential hypertension before and during treatment with oral arotinolol, bunazosin and prazosin, and these effects were compared with those in twenty-one patients treated with propranolol and labetalol in a previous studyα-Blockade with bunazosin and prazosin decreased systolic and diastolic blood pressure without any significant change in cardiac index (CI), and tended to reducetotal peripheral resitance index (TPRI). α, β-Blockade with labetalol tended to reduce heart rate and reduced TPRI without any change in CI. α, β-Blockade with arotinolol, which had weaker α-blocking activity than labetalol, reduced systolic and diastolic blood pressure, heart rate and CI, and increased TPRI. These effects appeared to be similar to those of β-blockade with propranolol . However, the increase in TPRI with propranolol was greater than that with arotinolol.These results suggest that vascular β-receptor blocking action may play a part in increasing peripheral resistance, while the α-blocking action on vascular sites may induce vasodilating action with a resultant decrease in TPRI or minimize elevated TPRI with vascular β-blockade according to their potency of the α-blocking activity.

ChemInform Abstract: STUDIES ON BENZENESULFONAMIDE DERIVATIVES WITH α‐ AND β‐ADRENERGIC ANTAGONISTIC AND ANTIHYPERTENSIVE ACTIVITIES

AbstractAuf dem im Formelschema angegebenen Weg werden die Sulfonamicle (V) hergestellt und deren α‐ und β‐Reze toren blockierende ä Wirkung und antih ertensive Ei enschaften untersucht.

Labetalol

• Labetalol hydrochloride is the prototype drug of a new class of antihypertensive agents that competitively and peripherally blocks both β- and α-adrenergic receptors. It possesses approximately one fourth of the β-blocking activity of propranolol hydrochloride and one half of the α-blocking activity of phentolamine. In humans, the effective β- to α-blocking activity is approximately 7:1. It has been used successfully In oral form to treat patients with mild, moderate, and severe hypertension and in intravenous form to manage hypertensive emergencies. Prominent side effects include orthostatic hypotension and gastrointestinal disturbances. Overall, the drug appears to offer several advantages over pure β-blocking drugs in some patients and should expand the armamentarium of the practicing physician in the management of the difficult hypertensive patient. (<i>Arch Intern Med</i>1983;143:485-490)

Labetalol. Current research and therapeutic status.

Labetalol hydrochloride is the prototype drug of a new class of antihypertensive agents that competitively and peripherally blocks both beta- and alpha-adrenergic receptors. It possesses approximately one fourth of the beta-blocking activity of propranolol hydrochloride and one half of the alpha-blocking activity of phentolamine. In humans, the effective beta- to alpha-blocking activity is approximately 7:1. It has been used successfully in oral form to treat patients with mild, moderate, and severe hypertension and in intravenous form to manage hypertensive emergencies. Prominent side effects include orthostatic hypotension and gastrointestinal disturbances. Overall, the drug appears to offer several advantages over pure beta-blocking drugs in some patients and should expand the armamentarium of the practicing physician in the management of the difficult hypertensive patient.

Studies on benzenesulfonamide derivatives with alpha- and beta-adrenergic antagonistic and antihypertensive activities.

New α-and β-adrenergic blockers, benzenesulfonamide derivatives (Ia-z), were prepared from acetylbenzenesulfonamides (II) by two methods. These compounds were tested for α-and β-blocking activities and their structure-activity relationships are discussed. All the target compounds have two asymmetric centers and therefore consist of two diastereomers. 5-[1-Hydroxy-2-[3-(2-methoxyphenyl)-1-methylpropylamino]ethyl]-2-methylbenzenesulfonamide (Ir) and 5-[1-hydroxy-2-[2-2-(2-methoxyphenoxy)-1-methylethylamino] ethyl]-2-methylbenzenesulfonamide (Iu) showed potent α-and β-blocking activities and they were each separated into two diastereomers (Ir-A and Ir-B, and Iu-A and Iu-B). It was found that one isomer had mainly β-blocking activity and the other isomer had mainly α-blocking activity. In addition, several compounds showing relatively strong α-and β-blocking activities were also examined for antihypertensive activity in conscious spontaneously hypertensive rats. Among the compounds tested, Ir and Iu were the most active, and they were more potent than labetalol. Compounds Ir and Iu may be of practical use as potent antihypertensive agents.

Pharmacological studies on supersensitization. III. Effect of potentiators on isolated tracheal preparation of guinea pig (author's transl)

Dose-response relationship of the effect of various potentiators to contraction and relaxation of isolated tracheal preparation of a guinea pig was examined and following results were obtained. (1) Cocaine augmented both contraction and relaxation induced by norepinephrine or epinephrine, but relaxation induced by aminophylline or papaverine was not influenced and that by isoproterenol or trimetoquinol decreased by cocaine. (2) Relaxation induced by norepinephrine or epinephrine was potentiated by chlorpromazine, phentolamine, and Dibenamine, while contractile responses induced by these catecholamines were not influenced by chlorpromazine, and abolished by phentolamine and Dibenamine at the same concentration range for inducing a dose-dependent augmentation of relaxation. This indicates that adrenergic α-blocking activity of these potentiators does not contribute to the augmentation of relaxation induced by catecholamines. (3) Cocaine also increased the sensitivity of tracheal preparation to acetylcholine without any effect on the level of maximum response, but dose-response relationship of cocaine for the potentiation of response to acetylcholine was not coincident to that to norepinephrine. (4) Higher concentration of cocaine decreased the level of maximum response of tracheal preparation to acetylcholine in low-calcium medium, but the mechanism of this inhibitory action remains unsolved.