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Analytical Chemistry Feb 2020Capillary electrophoresis-mass spectrometry is a powerful technique for high-throughput and high efficiency separations combined with structural identification....
Capillary electrophoresis-mass spectrometry is a powerful technique for high-throughput and high efficiency separations combined with structural identification. Electrospray ionization is the primary interface used to couple capillary electrophoresis to mass analyzers; however, improved designs continue to be reported. A new interfacing method based on vibrating sharp-edge spray ionization is presented in this work to overcome the challenges of decoupling applied voltages and to enhance the compatibility with separations performed at near-neutral pH. The versatility and ease of use of this ionization source is demonstrated using β-blockers, peptides, and proteins. The cationic β-blocker pindolol was injected electrokinetically, and detected at concentrations ranging from 10 nM to 5 μM, with an estimated detection limit of 2 nM. The vibrating sharp-edge spray ionization functions with flow rates from 70 to 200 nL/min and did not perturb the capillary electrophoresis separation electroosmotic flow as evidenced by the observation that most migration times differed less than 7% ( = 3) across a lab-built system interfaced to mass spectrometry and a commercial system that utilizes absorbance detection. For cationic beta-blockers the theoretical plates achieved in the capillary electrophoresis-mass spectrometry setup were 80%-95% of that observed with a commercial capillary electrophoresis-UV absorbance detection system.
Topics: Electroosmosis; Electrophoresis, Capillary; Molecular Structure; Pindolol; Spectrometry, Mass, Electrospray Ionization
PubMed: 31971372
DOI: 10.1021/acs.analchem.9b03994 -
Spectrochimica Acta. Part A, Molecular... May 2009Beta-adrenoceptor-blocking agents (beta-blockers) are on the list of the top selling drugs. Pindolol is a representative of this type of compound, either from the...
Beta-adrenoceptor-blocking agents (beta-blockers) are on the list of the top selling drugs. Pindolol is a representative of this type of compound, either from the structural point of view, or as reference for comparison of the pharmacokinetic properties of the beta-blockers. A study of the pindolol structure based on infrared spectroscopy and natural bond orbital (NBO) theory is the main aim of the present research. FTIR spectra of the solid pindolol were recorded from 4000 to 400cm(-1), at temperatures between 25 and -170 degrees C. For spectral interpretation, the theoretical vibrational spectra of the conformer present in the solid was obtained at the B3LYP/6-31G* level of theory. NBO analysis of the reference conformer, before and after optimization, was carried out at the same level of theory referred above. Characteristic absorption vibrational bands of the spectra of solid pindolol and of the isolated conformer were identified. Intra- and intermolecular interactions in pindolol were confirmed by the frequency shift of the vibrational modes and by the NBO theory. A detailed molecular picture of pindolol and of its intermolecular interactions was obtained from spectroscopy and NBO theory. The combination of both methods gives a deeper insight into the structure.
Topics: Adrenergic beta-Antagonists; Models, Chemical; Molecular Structure; Pindolol; Spectroscopy, Fourier Transform Infrared; X-Ray Diffraction
PubMed: 19129004
DOI: 10.1016/j.saa.2008.11.026 -
Journal of Medicinal Chemistry Oct 2011The growing practice of exploiting noninvasive fluorescence-based techniques to study G protein-coupled receptor pharmacology at the single cell and single molecule...
The growing practice of exploiting noninvasive fluorescence-based techniques to study G protein-coupled receptor pharmacology at the single cell and single molecule level demands the availability of high-quality fluorescent ligands. To this end, this study evaluated a new series of red-emitting ligands for the human β-adrenoceptor family. Upon the basis of the orthosteric ligands propranolol, alprenolol, and pindolol, the synthesized linker-modified congeners were coupled to the commercially available fluorophore BODIPY 630/650-X. This yielded high-affinity β-adrenoceptor fluorescent ligands for both the propranolol and alprenolol derivatives; however, the pindolol-based products displayed lower affinity. A fluorescent diethylene glycol linked propranolol derivative (18a) had the highest affinity (log K(D) of -9.53 and -8.46 as an antagonist of functional β2- and β1-mediated responses, respectively). Imaging studies with this compound further confirmed that it can be employed to selectively label the human β2-adrenoceptor in single living cells, with receptor-associated binding prevented by preincubation with the nonfluorescent β2-selective antagonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol (ICI 118551) ( J. Cardiovasc. Pharmacol.1983, 5, 430-437. ).
Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Alprenolol; Animals; Boron Compounds; CHO Cells; Cricetinae; Cricetulus; Drug Partial Agonism; Fluorescent Dyes; Genes, Reporter; Humans; Ligands; Microscopy, Confocal; Pindolol; Propranolol; Radioligand Assay; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2; Receptors, Adrenergic, beta-3; Single-Cell Analysis; Stereoisomerism; Structure-Activity Relationship
PubMed: 21870877
DOI: 10.1021/jm2008562 -
British Journal of Clinical Pharmacology Aug 19871 To compare the haemodynamic effects of secondary characteristics of beta-adrenoceptor blockers with an angiotensin converting enzyme inhibitor forty patients with... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Haemodynamic effects of atenolol, labetalol, pindolol and captopril: a comparison in hypertensive patients with special reference to changes in limb blood flow, heart rate and left ventricular function.
1 To compare the haemodynamic effects of secondary characteristics of beta-adrenoceptor blockers with an angiotensin converting enzyme inhibitor forty patients with previously untreated mild to moderate hypertension were prescribed either atenolol 50-100 mg day-1, labetalol 200-800 mg day-1, pindolol 10-30 mg day-1 or captopril 25-100 mg day-1 and observed for 6 months. 2 Over this period: (a) All four drugs produced similar reductions in blood pressure at rest (P less than or equal to 0.01) and after exercise (P less than or equal to 0.01). (b) All four drugs significantly decreased resting forearm (P less than or equal to 0.01) and calf blood flow (P less than or equal to 0.01). They all also caused a significant reduction in the increased calf blood flow following exercise (P less than or equal to 0.01). (c) No drug produced a change in resting forearm vascular resistance, while resting calf vascular resistance was decreased by captopril and pindolol, unaltered by labetalol and increased by atenolol. Post-exercise calf vascular resistance was increased by atenolol, labetalol and pindolol but unaltered by captopril. (d) Although all four drugs produced a fall in resting heart rate this was significantly greater for atenolol and labetalol (P less than or equal to 0.01). All four treatments however significantly reduced the increase in heart rate following exercise (P less than or equal to 0.01). (e) No drug produced any significant change in resting and post-exercise stroke volume/ejection fraction. 3 It is concluded that despite differing modes of action all four drugs reduce limb blood flow. This primarily appears to be a consequence of reduced perfusion pressure associated with limited autoregulation of skeletal muscle circulation. The reduction in arterial vascular resistance produced by captopril and pindolol is inconsistent and does not appear of major benefit in preserving limb blood flow. The reduction in perfusion with the agents studied may in part be related to a fall in cardiac output associated with decreased heart rate. This suggests that captopril may exert antisympathetic activity when used as an antihypertensive agent.
Topics: Adrenergic beta-Antagonists; Atenolol; Blood Pressure; Captopril; Female; Forearm; Heart; Heart Rate; Hemodynamics; Humans; Hypertension; Labetalol; Leg; Male; Middle Aged; Myocardial Contraction; Pindolol; Regional Blood Flow; Vascular Resistance
PubMed: 2887190
DOI: 10.1111/j.1365-2125.1987.tb03157.x -
The American Journal of Cardiology Apr 1986It is frequently hypothesized that drug-induced alterations in the density of beta-adrenergic receptors underlie tolerance to and physical dependence on agonists and...
It is frequently hypothesized that drug-induced alterations in the density of beta-adrenergic receptors underlie tolerance to and physical dependence on agonists and antagonists at beta-adrenergic receptors. Two approaches to determining the effect of treatment with drugs on the density of beta-adrenergic receptors are described. In the first, the density of beta-adrenergic receptors was measured on leukocytes taken from human subjects during and after drug treatment. Treatment with the antagonist propranolol caused an increase in the density of beta-adrenergic receptors on leukocytes, whereas treatment with the agonists terbutaline and ephedrine, or pindolol, an antagonist with intrinsic sympathomimetic activity, caused a decrease in the density of beta-adrenergic receptors. In the second approach, the effect of agonists on the density of beta-adrenergic receptors on C6 glioma cells in culture was determined. Incubation with the full agonist isoproterenol decreased the density of both beta 1- and beta 2-adrenergic receptors. In contrast, incubation with pindolol or celiprolol, also an antagonist with intrinsic sympathomimetic activity, selectively decreased the density of beta 2-adrenergic receptors. Pindolol and celiprolol may be useful in situations in which selective stimulation of beta 2-adrenergic receptors and blockade of beta 1-adrenergic receptors is desirable.
Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Celiprolol; Cells, Cultured; Ephedrine; Heart; Humans; Leukocytes; Pindolol; Propanolamines; Propranolol; Rats; Receptors, Adrenergic, beta; Terbutaline
PubMed: 2871741
DOI: 10.1016/0002-9149(86)90883-0 -
British Medical Journal Sep 1979
Topics: Humans; Lung; Male; Middle Aged; Pindolol; Pulmonary Fibrosis
PubMed: 497711
DOI: 10.1136/bmj.2.6190.581-a -
British Journal of Clinical Pharmacology 19821 Pindolol is a beta-adrenoceptor antagonist equally effective on beta 1- and beta 2-adrenoceptors which has a relatively long duration of action. It is practically... (Review)
Review
1 Pindolol is a beta-adrenoceptor antagonist equally effective on beta 1- and beta 2-adrenoceptors which has a relatively long duration of action. It is practically completely absorbed and, unlike most other beta-adrenoceptor blockers, is only metabolized to a small extent during the first passage through the liver. 2 Pindolol possesses partial agonist activity (intrinsic sympathomimetic activity, ISA). This means that apart from blocking beta-adrenoceptors it produces some stimulation. Pindolol therefore only slightly influences normal sympathetic drive at rest but effectively reduces the effects of elevated sympathetic activity. 3 Various therapeutic advantages have been attributed to the partial agonist activity of pindolol: no or only slight alterations in normal cardiac output, heart rate and peripheral blood flow occur. Peripheral resistance is reduced during chronic oral therapy. No alteration of HDL/LDL cholesterol ratio has been observed. Rebound phenomena on sudden withdrawal of therapy and bronchoconstriction in susceptible patients are less likely than with drugs devoid of ISA.
Topics: Adrenergic beta-Agonists; Animals; Heart Rate; Hemodynamics; Humans; Lung; Pindolol; Substance Withdrawal Syndrome
PubMed: 6125169
DOI: 10.1111/j.1365-2125.1982.tb01909.x -
British Journal of Pharmacology Feb 19961. Pindolol, cyanopindolol (CYP) and iodocyanopindolol (IodoCYP) have been reported to act either as antagonists, agonists or partial agonists at the beta 3-adrenoceptor...
1. Pindolol, cyanopindolol (CYP) and iodocyanopindolol (IodoCYP) have been reported to act either as antagonists, agonists or partial agonists at the beta 3-adrenoceptor in different preparations. A comprehensive investigation has not yet been described with these compounds tested in one tissue from one species. This study was conducted to delineate the pharmacological effects of pindolol, CYP and IodoCYP and to provide data on their affinities at the predominant beta-adrenoceptor in rat ileum. 2. The beta-adrenoceptors present in rat ileum were characterized in the presence of CGP 20712A and ICI 118 551, atropine and corticosterone, with (-)-isoprenaline used as an agonist. The role of the beta 1 and beta 2-adrenoceptors was determined by the omission of either CGP 20712A, ICI 118 551, or both, from the buffers. Conversely, the effectiveness of the beta 1- and beta 2-adrenoceptor blockade was examined by use of the beta 1-adrenoceptor-selective agonist, RO 363 and the beta 2-adrenoceptor-selective agonist, salbutamol. 3. There was no evidence for the presence of functional beta 1-adrenoceptors, and no strong evidence that beta 2-adrenoceptor stimulation contributed to the relaxant effects of (-)-isoprenaline. (-)-Phenylephrine did not produce relaxation of the tissue and 5-hydroxytryptamine produced contraction. 4. The beta 3-adrenoceptor-selective agonist, BRL 37344 and (-)-isoprenaline were potent full agonists (pD2 8.35 +/- 0.04 and 7.76 +/- 0.14 respectively), whereas ICI D7114 was less potent (pseudo pD2 6.92 +/- 0.15). These results indicate that the predominant functional beta-adrenoceptors in rat ileum are beta 3-adrenoceptors. 5. Partial agonist effects were produced by CYP (pD2 5.28 +/- 0.26) and IodoCYP (pD2 7.0 +/- 0.26), but not pindolol. All three compounds antagonized the effects of (-)-isoprenaline with pKb values of 6.68 +/- 0.10, 7.59 +/- 0.07 and 7.59 +/- 0.11 for pindolol, CYP and IodoCYP respectively. Likewise, CYP and IodoCYP antagonized the effects of BRL 37344 with pKb values of 7.20 +/- 0.22 and 7.21 +/- 0.14 respectively. This study provides the first functional data on the effects of IodoCYP, the ligand with the highest known affinity for the beta 3-adrenoceptor, at the characterized rat ileum beta 3-adrenoceptor. 6. In conclusion, whereas pKb values suggest that CYP and IodoCYP have a similar affinity for the beta 3-adrenoceptor in rat ileum, the higher potency of IodoCYP suggests that it promotes a greater coupling efficiency, or that its partial agonist effects are produced through a site other than the beta 3-adrenoceptor. The similar pKb values for CYP and IodoCYP at the beta 3-adrenoceptor contrast with their order of known affinities at the beta 1- and beta 2-adrenoceptors, where IodoCYP is far more potent than CYP. This provides evidence of further differences in the characteristics of the beta 3-adrenoceptors compared to the beta 1- and beta 2-adrenoceptors. Finally, the utility of IodoCYP as a beta 3-adrenoceptor antagonist would appear to be limited because of the greater magnitude of partial agonist effects that it produces.
Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Female; Ileum; In Vitro Techniques; Iodocyanopindolol; Male; Muscle Relaxation; Pindolol; Rats; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3
PubMed: 8646418
DOI: 10.1111/j.1476-5381.1996.tb15248.x -
British Journal of Clinical Pharmacology 1982The dose-response curve of pindolol on exercise heart rate has been constructed from observations in healthy male subjects studied 2 h after oral doses of pindolol 0.25... (Comparative Study)
Comparative Study
The dose-response curve of pindolol on exercise heart rate has been constructed from observations in healthy male subjects studied 2 h after oral doses of pindolol 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, 5 mg, 10 mg and 20 mg. This dose-response curve has been compared with historical controls who received atenolol, oxprenolol, practolol, propranolol and sotalol. The dose-response curves differ in the relative potency of the drug, the maximum reduction of heart rate and possibly in the slope of the curves. Pindolol is extremely potent. At doses which produce 15% reduction of exercise heart rate, the relative potencies of the drugs were: pindolol (1), atenolol (1:21) oxprenolol (1:19), practolol (1:44), propranolol (1:25) and sotalolol (1:160). The maximum effects produced by pindolol, oxprenolol and practolol were less than those of the other β-adrenoceptor blocking drugs, an effect which is probably the result of their partial agonist activity. Following intravenous pindolol 0.005, 0.01, 0.02 and 0.045 mg/kg the reduction of exercise heart rate and duration of action were dose-dependent. The effects of pindolol 0.045 mg/kg i.v. (mean total dose 3.5 mg), pindolol 5 mg p.o., propranolol 0.3 mg/kg i.v. (mean total dose 25.1 mg) and propranolol 80 mg p.o. were assessed on resting, standing and exercise heart rates. Neither drug reduced resting heart rate but propranolol reduced standing heart rate from 98.8 to 80.3 beats/min. The effects of all four preparations on exercise heart rate were similar. Oral pindolol is approximately 16-20 times as potent as oral propranolol. Intravenous pindolol is approximately 6-8 times as potent as intravenous propranolol.
Topics: Administration, Oral; Adult; Dose-Response Relationship, Drug; Heart Rate; Humans; Injections, Intravenous; Male; Physical Exertion; Pindolol
PubMed: 7104142
DOI: 10.1111/j.1365-2125.1982.tb01910.x -
British Medical Journal (Clinical... Nov 1982Intra-arterial ambulatory blood pressure was measured over 24 hours, in 34 patients with newly diagnosed hypertension, both before and after double-blind randomisation... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Intra-arterial ambulatory blood pressure was measured over 24 hours, in 34 patients with newly diagnosed hypertension, both before and after double-blind randomisation to treatment with atenolol (n=9), metoprolol (n=9), pindolol (n=9), or propranolol in its slow-release form (n=7). The dosage of each drug was adjusted at monthly clinic visits until satisfactory control of blood pressure was achieved (140/90 mm Hg or less by cuff) or the maximum dose in the study protocol was reached. A second intra-arterial recording was made after these drugs had been taken once daily at 0800 for three to eight months (mean 5.0+/-SD 1.4) and was started four hours after the last dose.At the end of the 24-hour recordings blood pressure was significantly lower with all four drugs. The extent to which the drugs reduced blood pressure, however, differed over the 24 hours. Atenolol lowered mean arterial pressure significantly throughout all 24 recorded hours, metoprolol for 12 hours, pindolol for 15 hours, and slow-release propranolol for 22 hours. Neither metoprolol nor pindolol lowered blood pressure during sleep. A significant reduction in heart rate was observed over 20 hours with atenolol, 20 hours with metoprolol, 10 hours with pindolol, and 24 hours with slow-release propranolol. Atenolol, metoprolol, and slow-release propranolol continued to slow the heart rate 24 hours after the last tablet was taken; this effect on heart rate, however, was not sustained throughout the second morning in those patients taking atenolol. Pindolol, the only drug studied that has intrinsic sympathomimetic activity, increased heart rate and did not lower blood pressure during sleep.Atenolol and slow-release propranolol are effective as antihypertensive agents over 24 hours when taken once daily, whereas metoprolol and pindolol may need to be taken more frequently. At times of low sympathetic tone, however, such as during sleep, beta-blockers with intrinsic sympathomimetic activity may raise heart rate and attenuate the fall in blood pressure with treatment.
Topics: Adolescent; Adult; Aged; Atenolol; Blood Pressure; Clinical Trials as Topic; Delayed-Action Preparations; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Male; Metoprolol; Middle Aged; Monitoring, Physiologic; Physical Exertion; Pindolol; Propanolamines; Propranolol; Random Allocation; Time Factors
PubMed: 6814568
DOI: 10.1136/bmj.285.6352.1387