阿齐利特类似物的合成及其抗心律失常活性研究

目的 设计合成阿齐利特类似物,并研究其体外抗心律失常活性。方法 以1-氨基海因盐酸盐(1)为原料,1与一系列醛进行缩合反应得到关键中间体1-(取代甲叉基)氨基海因(2);2与1,4-二溴丁烷或1,3-二溴丙烷反应生成3,3与一系列仲胺反应,再经成盐得到盐酸阿齐利特衍生物。结果 设计合成了未见文献报道的12个目标化合物,所有化合物均经过¹H-NMR谱及MS谱确证。结论 目标化合物5b、5h、5i、5j对离体心肌细胞具有III类抗心律失常药物延长动作电位时程的特征,其中化合物5h活性最好。     

Pharmacological activity of nitroxide analogues of dichloroisoproterenol and propranolol.

Spin-labeled analogues of dichloroisoproterenol and propranolol were synthesized. It was found that the KD's of both probes for the beta-adrenergic receptors of frog erythrocytes were about 30-fold higher than the KD's previously reported for the parent antagonists. Thus the introduction of a bulky nitroxide moiety in place of the isopropyl group on the amino nitrogen is associated with a decrease in affinity for the beta-adrenergic receptors. Nonetheless, the affinity of the spin-labeled propranolol would appear to be within a range compatible with EPR measurements.     

Investigation of the mechanism of negative inotropic activity of some calcium antagonists

An attempt was made to discriminate between calcium entry blockade and other calcium antagonistic mechanisms involved in the negative inotropic activity of nifedipine, verapamil, diltiazem, flunarizine, lidoflazine, and bepridil in isolated guinea pig hearts. For this purpose, we used the calcium entry promoter Bay K 8644 as a tool to modulate the process of calcium entry at the sarcolemmal level. The calcium ionophore A 23187 was employed to increase intracellular calcium content without interfering with calcium channels. Bay K 8644 interacted with nifedipine, verapamil, and diltiazem; however, only a small inhibitory effect on the negative inotropic responses of flunarizine, lidoflazine, and bepridil was observed. The positive inotropic response of A 23187 was not influenced by nifedipine and was only slightly decreased by verapamil or diltiazem. After addition of flunarizine, lidoflazine, or bepridil, however, the positive inotropic effect of A 23187 was completely abolished. These results suggest that the negative inotropic effects of the calcium entry blockers are not only the result of calcium entry blockade. Apparently, an additional calcium antagonistic effect also plays a role for flunarizine, lidoflazine, and for bepridil and, to a lesser degree, for verapamil and diltiazem.     

Prajmalium, an antiarrhythmic with positive inotropic effect: mechanism of action in rabbit single cardiomyocytes.

The propyl derivative of ajmaline, N-n-propylajamaline (prajmalium), is an antiarrhythmic compound that lacks the commonly reported negative inotropic effects of all others under clinical use. The present study was undertaken to establish and understand its effects at the cellular level in mammalian preparations. Electrical and mechanical activities were recorded from right ventricular strips and Na and L-type Ca currents (INa and ICaL, respectively) were recorded with the whole-cell patch-clamp technique in right ventricular myocytes freshly dissociated from rabbit hearts. Prajmalium decreased the maximal rate of depolarization of the action potential in a dose-dependent manner with an EC50 of 3 microM. This effect was use and frequency dependent. Action potential duration was increased by 1 microM prajamalium but decreased on applying higher concentrations. The force of contraction was slightly (15%) increased at 0.1 microM, not affected at all at 1 microM and depressed by 30% at 20 microM. In single cardiomyocytes maintained at negative holding potentials, INa was slightly depressed by prajmalium at 10 nM and reduced by 75% at 10 microM. ICaL was increased by 30 and 20% on applying prajmalium at 1 and 10 microM, respectively; on the other hand, ICaL was reduced by these two concentrations of prajmalium at less negative holding potentials. A higher prajmalium concentration (100 microM) decreased ICaL at all holding potentials studies and this effect was enhanced with depolarization. The increase in ICaL induced by prajmalium (1 microM) was also observed after ICaL had been fully beta-adrenergic and P2-purinergic stimulated by isoproterenol (1 microM) in the presence of IBMX (100 microM) and ATP (10 microM). It is concluded that prajmalium is able to increase ICaL in rabbit ventricular cells in a voltage-dependent manner, an effect that could account in part for the observed lack of negative inotropism of this antiarrhythmic in clinics.     

Relationship of structure to acute toxicity and antiarrhythmic activity in alkylamino- and dialkylaminoacet-ortho-toluidides

Translated from Khimiko-farmatsevtieheskii Zhurnal, Vol. 26, No. 4, pp. 51–55, April, 1992.     

Relationship between the stereoselective negative inotropic effects of verapamil enantiomers and their binding to putative calcium channels in human heart.

Ventricular preparations from patients with mitral disease and hypertrophic obstructive cardiomyopathy (HOCM) were set up to contract isometrically. Ventricular membrane particles were also prepared and putative calcium channels were labelled with [3H]-nimodipine. Positive staircase was induced by varying the rate of stimulation of isolated strips from 6 min-1 to 120 min-1 in the presence of 6-60 microM (-)-adrenaline or (-)-noradrenaline. (-)-Verapamil 3-5 microM or (+)-verapamil 20-30 microM reversed the force-frequency relationship (i.e. caused negative staircase) in preparations from patients with mitral disease or HOCM. In subendocardial strips of ventricular septum from 5 patients with HOCM paced at 60 min-1, both (-)-verapamil and (+)-verapamil caused cardiodepression. Half-maximal cardiodepression was observed with 0.4 microM (-)-verapamil and with 3 microM (+)-verapamil. [3H]-nimodipine bound to ventricular membrane particles in a saturable, reversible fashion to a high affinity site with an equilibrium dissociation constant of 0.23 nM. The density of these sites was 95 fmol mg-1 of membrane protein. Binding of the tritiated 1,4-dihydropyridine was stereoselectively inhibited by 1,4-dihydropyridine enantiomers and nifedipine. (-)-Verapamil and (+)-verapamil inhibited high affinity [3H]-nimodipine binding in a negative heterotropic allosteric manner with (-)-verapamil being 5 times more potent than (+)-verapamil on an IC50 basis. At a given [3H]-nimodipine concentration, (+)-verapamil inhibited a greater fraction of specific [3H]-nimodipine binding. The allosteric mode of (+)-verapamil inhibition of [3H]-nimodipine binding was confirmed by kinetic studies. (-)-Verapamil shifted (+)-verapamil-binding inhibition curves to the right in an apparently competitive fashion. The inversion of staircase caused by both verapamil enantiomers suggests that they cause a use-dependent channel blockade. The similar potency ratios for binding and for cardiodepression are indicative of a common locus of action for both verapamil enantiomers within the calcium channel.     

Design and synthesis of propranolol analogues as serotonergic agents

Serotonin (5-HT) binds with nearly identical affinity at the various central 5-HT binding sites. Few agents bind with selectivity for 5-HT1A sites. The beta-adrenergic antagonist propranolol binds stereoselectively both at 5-HT1A and 5-HT1B sites (with a several-fold selectivity for the latter) and, whereas it is a 5-HT1A antagonist, it appears to be a 5-HT1B agonist. As such, it could serve as a lead compound for the development of new 5-HT1A and 5-HT1B agents. The purpose of the present study was to modify the structure of propranolol in such a manner so as to reduce its affinity for 5-HT1B and beta-adrenergic sites while, at the same time, retaining its affinity for 5-HT1A sites. Removal of the side-chain hydroxyl group of propranolol, and conversion of its secondary amine to a tertiary amine, reduced affinity for 5-HT1B and beta-adrenergic sites. In addition, shortening the side chain by one carbon atom resulted in compounds with affinity for hippocampal 5-HT1A sites comparable to that of racemic propranolol, but with a 30- to 500-fold lower affinity for 5-HT1B sites and a greater than 1000-fold lower affinity for beta-adrenergic sites. The results of these preliminary studies attest to the utility of this approach for the development of novel serotonergic agents.     

ICI 181,037: a novel eukalemic diuretic with antiarrhythmic activity.

ICI 181,037, the most active compound from a series of 1,1-diarylcarbin-1-ol-2 amines, was evaluated for diuretic and cardiovascular activity. In saline-loaded rats, the magnitude of water diuresis and saluresis produced by ICI 181,037 (10 mg/kg, p.o.) was equal to that of hydrochlorothiazide. Water diuresis and saluresis produced by ICI 181,037 were enhanced with SKF 525A, ampicillin or neomycin plus lincomycin, suggesting that ICI 181,037 is an active diuretic. In conscious dogs, the saluretic activity of ICI d-181,037 (5 mg/kg, p.o.) was about 80% of the corresponding hydrochlorothiazide value, whereas the l-isomer demonstrated only minimum saluretic activity. In both rats and dogs, the concurrent kaliuresis after ICI 181,037 or its enantiomers was minimal as compared to hydrochlorothiazide. Following chronic dosing with diuretic doses, the basal levels of plasma potassium in dogs were not altered. In amphibian in vitro models for mimicking mammalian nephron, ICI 181,037 and its enantiomers demonstrated antinatriferic and antichloriferic activities, suggesting multiple renal sites of action for this agent. Racemic ICI 181,037 and its isomers reversed ouabain-induced arrhythmia in dogs and/or reduced the ouabain-induced mortality in mice after intravenous administration. It is concluded that ICI 181,037, particularly its d-isomer, is a novel eukalemic diuretic and possesses antiarrhythmic activity.     

Insights into the mechanism of action of ferroquine. Relationship between physicochemical properties and antiplasmodial activity

Ferroquine (FQ) is a 4-aminoquinoline antimalarial which contains a quinoline nucleus similar to chloroquine, but a novel ferrocenic group in its side chain. Previous work has demonstrated that this compound has excellent activity against malaria parasites, both in vitro and in vivo, with especially good activity against chloroquine-resistant parasites, but details of its mechanism of action have not previously been reported. In this study, we have investigated the physicochemical properties of FQ for comparison with chloroquine (CQ). Like CQ, FQ forms complexes with hematin in solution (log K = 4.95 +/- 0.05). FQ is an even stronger inhibitor of beta-hematin formation than CQ (IC(50) = 0.78 equiv relative to hematin for FQ vs 1.9 for CQ). These data suggest that the mechanism of action of FQ is likely to be similar to that of CQ and probably involves hematin as the drug target and inhibition of hemozoin formation. However, both the basicity and lipophilicity of FQ are significantly different from those of CQ. The lipophilicity of FQ and CQ are similar when protonated at the putative food vacuole pH of 5.2 (log D = -0.77 and -1.2 respectively), but differ markedly at pH 7.4 (log D = 2.95 and 0.85 respectively). In addition, the pK(a) values of FQ are lower (pK(a1) = 8.19 and pK(a2) = 6.99) than those of CQ (10.03 and 7.94, respectively). This suggests that there will be somewhat less vacuolar accumulation of FQ compared with CQ. Single crystal structure determination of FQ shows the presence of a strong internal hydrogen bond between the 4-amino group and the terminal N atom. This, together with the electron donating properties of the ferrocene moiety, probably explains the decreased pK(a). Interestingly, the decreased accumulation arising from the less basic behavior of this compound is partly compensated for by its stronger beta-hematin inhibition. Increased lipophilicity, differences in geometric and electronic structure, and changes in the N-N distances in FQ compared to CQ probably explain its activity against CQ-resistant parasites.     

Modulation of the negative inotropic effect of haloperidol by drugs with positive inotropic effects in isolated rabbit heart

Haloperidol is a typical antipsychotic drug with inhibitory effects on dopamine and calcium homeostasis. In this study, the effect of haloperidol on the inotropism of rabbits' isolated heart was investigated by measuring the isovolumetric left ventricular pressure using a balloon in a modified Langendorff perfusion apparatus. Haloperidol at 0.01-0.3 micromol/l induced a negative inotropic effect (E(max) = 77.95 +/- 0.19; EC(50) = 0.043 +/- 0.002 micromol/l). The effect of haloperidol was decreased by Ca(2+) (E(max) = 42.93 +/- 3.22; EC(50) = 0.37 +/- 0.07 micromol/l; pD'(2) = 7.01 +/- 0.16), Bay K 8644 (E(max) = 30.75 +/- 1.33; EC(50) = 10.43 +/- 1.5 micromol/l, pD'(2) = 7.13 +/- 0.12), and digoxin (E(max ) = 42.03 +/- 3.72, EC(50) = 0.32 +/- 0.05 micromol/l, pD'(2) = 6.81 +/- 0.14). The effect of haloperidol was also reduced by norepinephrine (E(max) = 37.16 +/- 1.84; EC(50) = 1.73 +/- 0.24 micromol/l, pD'(2) = 6.97 +/- 0.08) and dopamine (E(max) = 35.68 +/- 2.78; EC(50) = 0.69 +/- 0.01 micromol/l, pD'(2 )7.48 +/- 0.15). However, the effect of haloperidol was nonsignificantly reduced by dobutamine (E(max) = 58.89 +/- 5.18; EC(50) = 0.15 +/- 0.06 micromol/l, pD'(2) = 5.88 +/- 0.47). These results show that the drugs that increase the influx of Ca(2+) into the cardiomyocyte decrease the negative inotropic effect of haloperidol, suggesting that the effect of haloperidol could be mediated via mechanisms involving actions on Ca(2+) entry into the cardiomyocyte. Haloperidol should be used carefully when prescribed for patients with cardiovascular disorders.