[Beta-1 and beta-2 blocking activities of a new series of (arylalkoxy) propanolamines].
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Adrenergic beta-Antagonists↗
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Synthesis and beta-adrenergic antagonist activity of heterocyclic propanolamines.
The synthesis and beta-adrenergic antagonist activities of a group of 1-(heteroaryloxy)- and 1-(heteroaryl)-3-alkylamino-2-propanols is described. beta 1-Adrenolytic (atria) structure-activity correlations indicated that replacement of the 1-naphthyl moiety of propranolol by a 4-quinolyl- (10), 2-quinolyl- (24), or 2-pyrimidyl- (26) heterocyclic moiety resulted in a 10-16 fold reduction in activity. The 1-(4-quinolyloxy)- (10) and 1-(2-quinolyloxy)- (24-25) heteroaryl moieties provided more potent activity than the structurally related 1-[2-(2H-isoquinolin-1-one)]- (31-32) or 1-[3-(3H-quinazolin-4-one)]- (35-36) moieties. All compounds tested exhibited weak beta 2-adrenolytic activity on trachea. Although the most potent beta 1-antagonist, 1-(2-pyrimidyloxy)-3-isopropylamino-2-propanol (26), was 13-fold less potent than metoprolol, it exhibited a beta 1/beta 2 selectivity ratio superior to the cardioselective metoprolol.
Adrenergic beta-Antagonists↗
[o-Allyloxy-phenoxy-propanolamine, a new group of adrenergic beta-receptor blocking agents].
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Amino Alcohols↗
Deamination of 2-aminopropanol by ethanolamine ammonia-lyase, an AdoCbl-requiring enzyme. Kinetics and isotope effects for the R and S enantiomers of the substrate.
Both (R)-2-aminopropanol and (S)-2-aminopropanol are substrates for ethanolamine ammonia-lyase, reacting to yield propionaldehyde and ammonia via a common enzyme-bound intermediate. (S)-Propanolamine shows a lower Km and a higher Vmax than the R enantiomer, indicating that the former is a substantially better substrate than the latter. From the isotope effects and other considerations, it appears that the rate-limiting step for (S)-propanolamine is the same as that for ethanolamine, namely, the transfer of hydrogen from the cofactor to the product. In contrast, isotope effects seen with (R)-propanolamine indicate that there are two rate-limiting steps, both located in the segment of the reaction mechanism which is unique to the R enantiomer. One of these is the transfer of hydrogen from the substrate to the cofactor. The other is a subsequent step whose rate is similar to that of the first hydrogen transfer step but which does not involve the rupture of a carbon-hydrogen bond. It is speculated that this second rate-limiting step may have to do with the migration of the amino group.
Ammonia-Lyases↗
Phosphatidylethanolamine has an essential role in Saccharomyces cerevisiae that is independent of its ability to form hexagonal phase structures.
Two yeast enzymes, Psd1p and Psd2p, catalyze the decarboxylation of phosphatidylserine to produce phosphatidylethanolamine (PtdEtn). Mitochondrial Psd1p provides approximately 90% of total cellular phosphatidylserine decarboxylase activity. When the PSD1 gene is deleted, the resultant strain (psd1Delta) grows normally at 30 degrees C in glucose and in the absence of exogenous choline or ethanolamine. However, at elevated temperature (37 degrees C) or on the nonfermentable carbon source lactate, the growth of psd1Delta strains is minimal without ethanolamine supplementation. The reduced growth and viability correlate with a PtdEtn content below 4% of total phospholipid. These results suggest that there is a critical level of PtdEtn required to support growth. This theory is supported by growth data revealing that a psd1Delta psd2Delta dpl1Delta strain can only grow in the presence of ethanolamine. In contrast, a psd1Delta psd2Delta strain, which makes low levels of PtdEtn from sphingolipid breakdown, can be rescued by ethanolamine, choline, or the ethanolamine analogue propanolamine. psd1Delta psd2Delta cells grown in 2 mm propanolamine accumulate a novel lipid, which was determined by mass spectrometry to be phosphatidylpropanolamine (PtdPrn). PtdPrn can comprise up to 40% of the total phospholipid content in supplemented cells at the expense of phosphatidylcholine and PtdEtn. The absolute level of PtdEtn required for growth when PtdPrn is present appears to be 1% of the total phospholipid content. The essential function of the PtdEtn in the presence of propanolamine does not appear to be the formation of hexagonal phase lipid, insofar as PtdPrn readily forms hexagonal phase structures detectable by (31)P NMR.
Chromatography, Liquid↗
The mechanism of action of ethanolamine ammonia-lyase, an adenosylcobalamin-dependent enzyme. The source of the third methyl hydrogen in the 5'-deoxyadenosine generated from the cofactor during catalysis.
Ethanolamine ammonia-lyase is an adenosylcobalamin-dependent enzyme which catalyzes the conversion of ethanolamine and propanolamine to ammonia and the corresponding aldehydes. A mechanism has been proposed for this and other adenosylcobalamin-dependent reactions which involves cleavage of the carbon-cobalt bond of the cofactor followed by abstraction of a substrate hydrogen atom by the adenosyl fragment to form 5'-deoxyadenosine. In support of this proposal, a previous study demonstrated that the deamination of propanolamine by ethanolamine ammonia-lyase is accompanied by the reversible cleavage of the carbon-cobalt bond of the cofactor, with the production of 5'-deoxyadenosine (Babior, B.M., Carty, T.J., and Abeles, R.H. (1974) J. Biol. Chem. 249, 1689-1695). The present study is concerned with the origin of the third hydrogen atom on the methyl group of the 5'-deoxyadenosine produced in that reaction. The 5'-deoxyadenosine isolated from an incubation mixture initially containing enzyme, [5',5'-D2]adenosylcobalamin, and [1,1-D2]propanolamine was chemically degraded so that the 4' and 5' carbon atoms were, respectively, converted to the carbonyl and methyl carbons of acetaldehyde. Analysis of the p-nitrophenylhydrazone of the acetaldehyde by gas-liquid chromatography-mass spectroscopy revealed 3 deuterium atoms/molecule, indicating that two of the methyl hydrogens originated from adenosylcobalamin and the third was donated by substrate. This observation provides further support for the participation of 5'-deoxyadenosine in the mechanism of adenosylcobalamin-dependent reactions.
Ammonia-Lyases↗
NMR and calorimetric studies of changes in phase transition of head group modified phospholipids.
The 13C- and 31P-NMR spectra and DSC thermograms of unsonicated dispersions consisting of phospholipids of varying methylation stages of the propanolamine head group were investigated. Methylation of the head group was accompanied by a corresponding reduction in the phase transition temperatures. In the liquid crystalline state the 31P-anisotropy of the chemical shift is about equal for all studied compounds, demonstrating that the motion of the phosphate group is not influenced by modifications of the propanolamine group.
Calorimetry↗
The use of complexation with alkanolamines to facilitate skin permeation of mefenamic acid.
The preparation of mefenamic acid (MH)-alkanolamine [monoethanolamine, diethanolamine, triethanolamine and propanolamine] complexes was attempted to increase the transdermal flux of MH. A lipophilic enhancer system consisting of isopropyl myristate (IPM) and ethanol (9:1; EI system) produced a marked enhancement of MH flux from the alkanolamine complexes through hairless rat skin membrane. Among the alkanolamines examined, the propanolamine complex had the greatest enhancing effect on the permeation of MH. The observed permeation enhancement of MH-alkanolamine complexes by the EI system was explained by an analysis based on a two-layer diffusion model. The stratum corneum immersed in IPM forms a continuous phase of vehicle and stratum corneum and, from the phase, ethanol transport the MH-alkanolamine complexes to the epidermis and dermis, and the complexes, which are more water soluble than MH, exhibit increased partition into the epidermis and dermis, as the flux increases.
1-Octanol↗
Adrenergic agents. 8.1 Synthesis and beta-adrenergic agonist activity of some 3-tert-butylamino-2-(substituted phenyl)-1-propanols.
Replacement of the benzylic hydroxyl group of N-tert-butylnorepinephrine with a hydroxymethyl substituent affords a propanolamine homologue which retains a high degree of beta-adrenergic agonist activity. As modification of the meta substituent of catecholic ethanolamines, such as N-tert-butylnorepinephrine, often provides compounds that exert a more pronounced effect in relaxing tracheobronchial smooth muscle (beta2-adrenergic agonist) than in stimulating cardiac muscle (beta1-adrenergic response), a series of 3-tert-butylamino-2-(3-substituted 4-hydroxyphenyl)-1-propanols was prepared. The 3-meta substituents included HOCH2 (1b), H2NCONH (1c), MeSO2NH (1d), H (le), and NH2 (1f). These phenylpropanolamine derivatives were compared with their phenylethanolamine counterparts in in vitro tests that measure the ability of these compounds to relax spontaneously contracted guinea pig tracheal smooth muscle (a measure of potential bronchodilating activity) and to increase the rate of contraction of a spontaneously beating guinea pig right atrial preparation (an indicator of potential cardiac stimulating activity). In these tests all of the propanolamine derivatives included in the study were less potent than their ethanolamine relatives. In both series replacement of the catecholic m-hydroxyl group with the indicated substituents usually resulted in compounds with increased selectivity for tracheobronchial vs. cardiac muscle.
Adrenergic beta-Agonists↗
Some general influences of n-decylmethyl sulfoxide on the permeation of drugs across hairless mouse skin.
The influences of n-decylmethyl sulfoxide (NDMS) on the permeation of phenyl propanolamine, propranolol, acyclovir, and hydrocortisone through hairless mouse skin were investigated. Permeation of these compounds increased systematically with increasing NDMS concentration up to a limiting value for the permeability coefficient of about 0.1 cm/h. Permeability coefficients obtained with stripped skin indicated that, where NDMS has its maximal effect, the compounds diffuse through the skin as if there were no stratum corneum. Diffusion lag times of the test compounds through skin sections exposed to NDMS were far shorter than lag times in control experiments. The kinetics of NDMS action were assessed by pretreating skin sections for various periods of time with the enhancer and then assessing permeability. When applied as a 10 mM aqueous solution, the full effect of NDMS was obtained in 3 h of exposure and the effect lasted for at least 24 h. Treating the skin with ethanol/water (2:1) to elute NDMS after the pretreatment did not diminish its effect. Propranolol and phenyl propanolamine solubilized NDMS, presumably through the formation of mixed micelles, which had a profound effect on the permeation rates of both drug and enhancer.
Acyclovir↗
Use of phthaloyl protecting group for the automated synthesis of 3'-[(hydroxypropyl)amino] and 3'-[(hydroxypropyl)triglycyl] oligonucleotide conjugates.
The chemical stability of oligonucleotides (ODNs) containing 3'-propanolamine was investigated. Invariably, all the ODNs synthesized from Fmoc-protected 3-aminopropane-1,2-diol-CPG support gave a mixture of three compounds at the end of automated synthesis as analyzed by denaturing PAGE and HPLC. On the basis of analytical procedures, these compounds were identified to be 3'-[N-acetyl-N-(hydroxypropyl)amino],3'-[(hydroxypropyl)amino], and 3'-hydroxyl ODNs. The instability of the amino protecting group under the synthesis conditions was responsible for this observed heterogeneity. In order to evaluate the stability, a comparative study on the chemical stability of the ODN containing amino-protecting groups such as [(9-fluorenylmethyl)oxy]carbonyl (Fmoc), trifluoroacetyl (TFA), and phthaloyl was undertaken. The results indicate that the phthaloyl group provided the best stability for the synthesis of 3' amine-modified ODNs, and the protecting group is cleaved and deprotected in concentrated ammonium hydroxide:40% aqueous methylamine, 1:1, for 5-10 min, at 56 degrees C. The 3'-hydroxypropyl)triglycyl] ODN conjugates were also synthesized from Fmoc- and phthaloyl-protected (hydroxypropyl)triglycine-CPG supports.
Base Sequence↗
Guaiacoxypropanolamine derivatives of capsaicin: a new family of beta-adrenoceptor blockers with intrinsic cardiotonic properties.
A series of guaiacoxypropanolamine derivatives of capsaicin was synthesized by replacing the phenolic OH of N-nonanoylvanillamide with epichlorohydrin, followed by cleavaging the obtained epoxide compound with alkylamines. Intravenous injection of these propanolamine derivatives (1 mg/kg) in normotensive Wistar rats induced a transient fall in blood pressure but significantly reduced the heart rate for more than 30 min. These derivatives (10(-8)-10(-6) M) inhibited isoproterenol (10(-10)-10(-5) M)-induced positive chronotropic and inotropic effects in isolated guinea pig atrium. On the other hand, these derivatives (10(-5)-10(-4) M) exhibited a positive cardiotonic effect that is independent of intrinsic sympathomimetic effects. Investigation of the structure-activity relationship of these derivatives revealed that the position of the oxypropanolamine side chain and substituents of the 4-OH position play significant roles in imparting their pharmacological effects. Of the derivatives tested, the most effective one was compound 9. In conclusion, the results obtained from in vitro and in vivo studies suggested that these derivatives and compound 9 may be expected to be beta-adreneoceptor blocking agents with nonadrenergic positive chronotropic and inotropic properties.
Adrenergic beta-Antagonists↗
Flavones. 2. Synthesis and structure-activity relationship of flavodilol and its analogues, a novel class of antihypertensive agents with catecholamine depleting properties.
(3-Phenyl-7-flavonoxy)propanolamines have been shown to exhibit antihypertensive activity in spontaneously hypertensive rats. Although they are structurally similar to classical beta-adrenergic blocking compounds, their activity is not due to inhibition of beta-adrenoceptors. In the present study, a series of simple flavonoxypropanolamines was prepared to further explore the structural requirements for the antihypertensive effect of these compounds. A structure-activity relationship of these derivatives indicates that the position of the oxypropanolamine side chain, the hydroxy group of the side chain, steric bulkiness and length of N substituents, degree of the N-substitution, phenyl group at the 2-position of the chromone nucleus, and substituents of the phenyl group or B ring of the flavone play significant roles in imparting pharmacological effects. In addition, there is a good correlation between the antihypertensive activity and depletion of myocardial norepinephrine. Of these analogues tested, the most effective one was flavodilol. Only the 8-substituted analogue 6 was found to be a beta-antagonist. Flavodilol was chosen for in-depth pharmacological, toxicological, and clinical evaluation.
Adrenal Glands↗
Beta-adrenergic blocking agents. 20. (3-Hydroxyprop-1-enyl)-substituted 1-(aryloxy)-3-(alkylamino)propan-2-ols.
The synthesis of a series of (3-hydroxyprop-1-enyl)-substituted 1-(aryloxy)-3-(alkylamino)propan-2-ols is described. These compounds were investigated for their beta-adrenoreceptor blocking properties and their selective of action. Among the o-(hydroxypropenyl)-substituted derivatives we have found some potent noncardioselective beta-adrenoreceptor blocking agents which have a greater blocking action on the beta 2 receptor, thus resembling propranolol. The p-(hydroxypropenyl)-substituted analogues were generally less potent and tended to be cardioselective. The structure-activity relationships are discussed in the light of the hypothesis that the cardioselective of p-amido-substituted (aryloxy)propanolamines is attributable, in part, to binding of the amide group to some additional site on the beta receptor; our findings argue against a similar interaction for the allylic hydroxyl group.
Adrenergic beta-Antagonists↗
beta 1-selective adrenoceptor antagonists. 2. 4-ether-linked phenoxypropanolamines.
A series of 4-substituted phenoxypropanolamines was prepared and examined for beta-adrenoceptor activity. Some of the compounds, especially the [4-[2-[[2-(4-fluorophenyl)ethyl] oxy]ethoxy]phenoxy]propanolamines (14, 15, and 24), showed potent beta 1-blockade with virtually no beta 2-blockade at doses over a 1000 times greater. The compounds also possessed partial agonist activity. Structure-activity relationships are discussed, and conclusions are drawn about the binding sites on beta-adrenoceptors.
Adrenergic beta-Agonists↗
Beta-adrenergic blocking agents: substituted phenylalkanolamines. Effect of side-chain length on beta-blocking potency in vitro.
The synthesis of a group of potential beta-blockers bearing a new 5-ethoxysalicylamide substituent on nitrogen is described. These compounds were tested for beta-adrenergic blocking potency in vitro and compared with analogous compounds bearing a tert-butyl group on nitrogen. The new N-substituent increased the beta-blocking potency substantially. In a series of five homologous compounds of the type Ar(CH2)nCHOHCH2NHR (R = 5-ethoxysalicylamide; n = 0-4), two maxima of beta-blocking potency were found for n = 0 and 2. Moreover, the carbon isostere of the corresponding (aryloxy)propanolamine still proved to be a very potent beta-blocker. The ether oxygen in the side chain is therefore not an absolute requirement for activity. Structure-activity relationships are discussed.
Adrenergic beta-Antagonists↗
Phosphatidylcholine and N-methylated phospholipids are nonessential in Saccharomyces cerevisiae.
Phosphatidylcholine (PtdCho) is the most abundant phospholipid in numerous eukaryotes and is generally thought to be essential for membrane structure and cellular function. We designed a specific test of this idea by using genetic and biochemical manipulation of yeast. Yeast mutants (pem1 pem2Delta) lacking the phosphatidylethanolamine (PtdEtn) methyltransferase enzymes require choline for growth and cannot make N-methylated phospholipids. When these strains are grown on a glucose carbon source supplemented with 20 mm propanolamine (Prn), the PtdCho level declines precipitously to the limits of detection (<0.6%), and the hexagonal phase-forming, primary amine-containing lipids, PtdEtn and PtdPrn, constitute approximately 60% of the total phospholipid content of the cell. When the lipids were analyzed by mass spectrometry, there was no compensatory shift in unsaturation of the PtdEtn and PtdPrn toward more bilayer-forming species. Thus the majority of the cellular amino phospholipids remained hexagonal phase-forming. The pem1 pem2Delta cells will also grow without choline, in the presence of Prn, on nonfermentable carbon sources (requiring functional mitochondria) and accumulate nearly 70% of their phospholipid as hexagonal phase-forming types. These data provide compelling evidence that the functions of PtdCho and N-methylated lipids in membranes are nonessential in Saccharomyces cerevisiae.
Choline↗
[Effect of a new beta-blocker (CM 6805) on the action potential of guinea pig atrial fiber].
CM6804 effect has been studied about some parameters of the intracellular action potential (AP) of guinea pig autorythmic auricle. Auricle was preserved alive under Tyrode oxygenated solution at 37 degrees C. AP is measured by a fluctuating intracellular glass microelectrode. At a concentration of 5 . 10(-5) M, CM doesn't alter the resting membrane potential, it causes a small overshoot reduction, it decreases the maximum depolarization rate and the heart rate, it increases the action potential duration. Overshoot and maximum depolarization rate decrease prove that CM modifies the membrane permeability probably by a diminution of the sodium rapid inward current. CM action is similar to others aryl-oxy-propyl propanolamine like propranolol.
Action Potentials↗