(+)-Penbutolol ((R)-Penbutolol)
(Synonyms: (R)-Penbutolol; (+)-Isopenbutolol) 目录号 : GC31597(+)-Penbutolol ((R)-Penbutolol) 是一种 β-adrenoceptor 拮抗剂,IC50 为 0.74 μM。
Cas No.:38363-41-6
Sample solution is provided at 25 µL, 10mM.
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(+)-Penbutolol is a β-adrenoceptor antagonist, with an IC50 of 0.74 μM[1]. (+)-Penbutolol is an optical isomer of l-penbutolol with Na+ channel-blocking action[2].
(+)-penbutolol on the [Ca2+]i-increase induced by LPC is concentration-dependent[1].(+)-penbutolol inhibits the rounding of cells dose dependently (8±4%, 56±4% and 66±2% at the concentrations of 10-6 M, 5×10-6 M and 10-5 M, respectively)[2].
[1]. Chen M, et al. Effects of beta-adrenoceptor antagonists on Ca(2+)-overload induced by lysophosphatidylcholine in rat isolated cardiomyocytes. Br J Pharmacol. 1996 Jun;118(4):865-70. [2]. Hashizume H, et al. Effects of antiischemic drugs on veratridine-induced hypercontracture in rat cardiac myocytes. Eur J Pharmacol. 1994 Dec 12;271(1):1-8.
Cas No. | 38363-41-6 | SDF | |
别名 | (R)-Penbutolol; (+)-Isopenbutolol | ||
Canonical SMILES | O[C@@H](COC1=C(C=CC=C1)C2CCCC2)CNC(C)(C)C | ||
分子式 | C18H29NO2 | 分子量 | 291.43 |
溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 3.4314 mL | 17.1568 mL | 34.3136 mL |
5 mM | 0.6863 mL | 3.4314 mL | 6.8627 mL |
10 mM | 0.3431 mL | 1.7157 mL | 3.4314 mL |
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Mutagenicity of enantiomers of penbutolol
With a view to examine the effect of chirality and the cause of batch-to-batch variation in the mutagenicity of penbutolol, penbutolol enantiomers - isopenbutolol [R(+)-enantiomer] and penbutolol [S(-)-enantiomer] - and two batches of Betapressin were tested employing the Ames Salmonella tester strain TA98. The mutagenic activity of R(+)-enantiomer was found to be similar to that of a batch of penbutolol with a high content of this optical isomer. The pharmaceutical form of penbutolol, Betapressin, exhibited either less or equal mutagenic effectiveness to the S(-)-enantiomer. In the presence of the S9 mix, the mutagenicity of R(+)-enantiomer was only slightly affected in the low dose range of 40 to 160 micrograms/plate. A metabolite of penbutolol, (RS) l"-dehydropenbutolol, did not cause an increase in the number of revertants/plate.
Absence of genotoxic activity of penbutolol in bacterial and mammalian cell screening systems
The genotoxic potential of the beta-adrenergic blocker penbutolol was assessed using the Ames and HGPRT tests, unscheduled DNA synthesis (UDS) and alkaline elution assays. In the Ames test, penbutolol was tested for cytotoxicity and genotoxic activity in concentration ranges of 0.8-500 micrograms/plate and 0.1-125 micrograms/ml in the HGPRT, UDS and alkaline elution assays. In the Ames test penbutolol showed significant toxicity above 500 micrograms/plate. In the mammalian cells (V79) used for the HGPRT test and A459 cells used for alkaline elution and UDS assays, penbutolol was cytotoxic at concentrations above 30 micrograms/ml. In another series of experiments, male Wistar rats were treated i.p. with penbutolol (1, 10 and 100 mg/kg) and after 2 h liver nuclei were isolated and formation of single DNA-strand breaks was measured. The results of the present study demonstrate the absence of genotoxic activity of penbutolol in the 5 strains of Salmonella typhimurium (TA98, TA100, TA1535, TA1537 and TA1538) and in the strain of Escherichia coli WP2 uvrA in the presence or absence of metabolic activation. In V79 cells, penbutolol showed no mutagenic effects at the HGPRT locus in the presence or absence of metabolic activation. Additionally, no significant incorporation of [3H]thymidine into the DNA in the UDS test or formation of DNA-strand breaks in the alkaline elution assay was detected in the non-toxic concentration range of penbutolol with or without metabolic activation. Furthermore, penbutolol did not cause DNA damage in liver nuclei isolated from penbutolol-treated rats.
Plasma protein binding of penbutolol in pregnancy
Penbutolol is a not cardioselective beta-adrenergic blocking drug; it is lipid soluble and differs in its protein binding from the other members of its group because shows linkage to alpha 1-glycoprotein, with no detectable binding to albumin. AAG levels change during pregnancy and so the binding of [3H]-penbutolol was compared in 11 pregnant patients and in 10 healthy women. Binding was obtained by ultrafiltration and measurement of the free fraction by scintillation spectrometry. The free penbutolol fraction was significantly higher in the pregnant women than in the controls (6.06 +/- 0.34 compared with 3.55 +/- 0.29, P less than 0.001). The AAG levels in the pregnant women were significantly lower (0.40 +/- 0.03 g/l) than in the controls (0.77 +/- 0.06 g/l) (P less than 0.001) which showed a significant correlation with the bound/free penbutolol ratio (r = 0.61, P less than 0.005). On the other hand there was no significant correlation with the extent of penbutolol's protein binding even though the albumin levels were lower in the pregnant women (2.83 +/- 0.17 compared with 4.86 +/- 0.17; P less than 0.001). Penbutolol's nK1a for AAG was lower in pregnant women, and this suggests that the fall in AAG levels is not the only factor involved in the reduced binding of penbutolol in pregnancy.
[Extent of beta-blocking action of S- and R-penbutolol during exercise testing (author's transl)]
The effect of 40 mg penbutolol (pure S-form = laevo penbutolol) and 40 mg isopenbutolol (pure R-form) on heart rate and blood pressure during exercise testing was investigated under double-blind, randomized, placebo-controlled conditions in 9 probands. 1.5 and 5.5 hours after ingestion of 40 mg penbutolol, resting, standing, exercise, and recovery heart rate as well as systolic pressure during exercise displayed a significant decline. Diastolic blood pressure rose slightly 1.5 hours after penbutolol. Isopenbutolol had no significant effect on resting and standing heart rate. 1.5 hours after ingestion, a slight reduction in exercise and recovery heart rate could be confirmed. The decline, however, was significantly lower than that achieved with penbutolol. In comparison with its dextrorotatory isomer, isopenbutolol, penbutolol has an approximately 100-fold more potent effect on exercise heart rate. This is also reflected in the drug's duration of action.
Behavioral effect of beta-blocking drugs resulting from the stimulation or the blockade of serotonergic 5-HT1B receptors
The present study was aimed at determining the relative potency of various beta-blocking drugs as agonists or antagonists at 5-HT1B receptors. The behavioral model used (increase in escape attempts of isolated mice) has been previously shown to be exclusively responsive to 5-HT1B agonists such as 1-3-(trifluoromethyl) phenylpiperazine (TFMPP). Beta-blocking drugs acted in three different ways: they were either inactive, or acted as agonists or as antagonists at 5-HT1B receptors. The specific beta-blocking drugs: atenolol and betaxolol (beta-1) and ICI 118,551 (beta-2) were inactive by themselves and in interaction with TFMPP. The mixed beta-1 beta-2 blocking drug 1-penbutolol, (but not d-penbutolol), inactive alone, behaved as an antagonist: it impaired in a dose-dependent way the effect of TFMPP. (+/-)Pindolol and (-)pindolol was inactive. None of the (-), (+), or (+/-)pindolol was able to impair TFMPP effect. The increase in escape attempts induced by (+/-)pindolol was antagonized with 1-penbutolol or after a specific desensitization. Cyanopindolol and S-tertatolol (but not R-tertatolol) acted as agonists. SDZ 21009 was inactive as agonist or antagonist. It may be concluded that all beta-blocking drugs are not equivalent regarding their effect at 5-HT1B receptors. L-penbutolol was the only drug acting as an antagonist.