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At least 19 recordsLinked to original sources
PubMed1987

Role of the (acyloxy)methyl moiety in eliciting the adrenergic beta-blocking activity of 3-(acyloxy)propanolamines.

Some totally aliphatic 3-(acyloxy)propanolamines were synthesized with the aim of testing whether beta-blocking activity could be obtained from this class of drugs, even in the absence of an aromatic group. The significant and, in most cases, competitive beta-blocking activity shown by the compounds under examination, together with the results of a theoretical study in which their reactivity was compared with that of other adrenergic beta-blocking drugs, seems to confirm a hypothesis previously advanced on the basis of knowledge about the action mechanism of adrenergic beta-blocking drugs and of the results of structural studies. It was also possible to suggest some considerations about the role played by the (acyloxy)methyl portion of 3-(acyloxy)propanolamines in eliciting their adrenergic beta-blocking activity.

Adrenergic beta-Agonists↗
PubMed1991

The synthesis and potassium channel blocking activity of some (4-methanesulfonamidophenoxy)propanolamines as potential class III antiarrhythmic agents.

The synthesis of 22 (4-methanesulfonamidophenoxy)propanolamines and their testing on isolated guinea pig cardiac myocytes, on isolated preparations from guinea pig atria, and on rat blood pressure are described. Secondary amines in the series (11a-f) showed residual beta-blocking activity, whereas incorporation of N-methyl phenylalkyl and 4-phenyl alicyclic amine groups abolished beta-blocking activity but led to enhanced ability to block the channel conducting the delayed rectified potassium current, and hence produced an increase in the cardiac action potential duration (APD). Incorporation of hydrophobic Cl and CF3 groups further enhanced potassium channel blocking activity. Compounds 81 and 8m produced a significant increase in APD at nanomolar concentrations, with no effect on cardiac muscle conduction velocity, and hence merit further investigation as Class III antiarrhythmic agents. Methylation of the methanesulfonamido group abolished channel-blocking activity; 4-carboxy and 3-methanesulfonamido analogues retained activity but at a reduced level.

Animals↗
PubMed1991

Synthesis and selective class III antiarrhythmic activity of novel N-heteroaralkyl-substituted 1-(aryloxy)-2-propanolamine and related propylamine derivatives.

The synthesis and biological evaluation of a series of novel 1-(aryloxy)-2-propanolamines and several related deshydroxy analogues are described. Compounds 4-29 were prepared and investigated for their class III electrophysiological activity in isolated canine Purkinje fibers and in anesthetized open-chest dogs. None of these compounds showed any class I activity. On the basis of the in vitro data, structure-activity relationships for the series are discussed. Two compounds, N-[4-[2-hydroxy-3-[methyl(2-quinolinylmethyl)amino] propoxy]phenyl]methanesulfonamide (12,WAY-123,223) and N-[2-[[methyl[3-[4-[(methylsulfonyl)amino]phenoxy]propyl] amino]methyl]-6-quinolinyl]-methanesulfonamide (24, WAY-125,971) were identified and characterized as potent and specific class III antiarrhythmic agents in vitro and in vivo. Compound 12 was found to be orally bioavailable, to produce large increases of ventricular fibrillation threshold (VFT), and, in some instances, to restore sinus rhythm from ventricular fibrillation in anesthetized open-chest dogs at a dose of 5 mg/kg (iv). The enantiomers of 12 (i.e., 13 and 14) were synthesized and were found to exhibit similar electrophysiological effects in the Purkinje fiber screen. Compound 24, a propylamine analogue with potency and efficacy comparable to those of UK-68798 (2) and E-4031 (3), was studied in voltage-clamp experiments (isolated cat myocytes) and was found to be a potent and specific blocker of the delayed rectifier potassium current (IK).

Animals↗
PubMed1990

Synthesis of novel (aryloxy)propanolamines and related compounds possessing both class II and class III antiarrhythmic activity.

Several (aryloxy)propanolamines and related compounds (i.e. 5-13, 16-18, 20-24, 27-33, 35, 37-39, 41, and 42) were synthesized and investigated for their class III electrophysiological activity and class II (beta-blocking) effects with use of in vitro and in vivo models. Structure-activity relationships are discussed for a series of 30 compounds. A number of these compounds prolonged the action potential duration at 95% repolarization of isolated canine cardiac Purkinje fibers by 20% (C20APD95) at concentrations of less than 1.0 microM, with no significant effects on cardiac conduction. beta-Adrenergic receptor binding studies showed that some of these compounds were 2-20 times more potent for cardiac beta 1 receptors than for beta 2 receptors. In particular, compounds 32, 41, 1, and especially (S)-1 were found to be orally active class III agents in anesthetized mongrel dogs (1 or 3 mg/kg, id) and efficacious at suppressing programmed electrical stimulation induced arrhythmias in halothane-anesthetized dogs. The profile of these compounds was similar to that found for sotalol. Compound (S)-1, which was more potent than sotalol in the PES study and equieffective in the halothane/epinephrine dog model, is being investigated further as a combined class III/II antiarrhythmic agent.

Action Potentials↗
PubMed1987

Flavones. 1. Synthesis and antihypertensive activity of (3-phenylflavonoxy)propanolamines without beta-adrenoceptor antagonism.

The synthesis of a series of (3-phenylflavonoxy)propanolamines is described. These compounds were evaluated for potential antihypertensive activity in spontaneously hypertensive rats, as well as for in vivo and in vitro evidence of beta-adrenoceptor antagonism. Some of the compounds of this series exhibited effective antihypertensive properties but did not antagonize beta-adrenergic receptors. These active compounds represent a unique series of effective antihypertensive agents that, despite possessing structural characteristics typical of beta-blockers, does not have beta-adrenergic receptor blocking activity.

Adrenergic beta-Antagonists↗
PubMed1989

A new series of tricyclic (aryloximino)propanolamines displaying very high selective beta 2-blocking properties.

A new class of indanones 4 easily obtained by aryne type condensations, followed by transposition of the benzocyclobutanols 3 thus formed, were transformed into the corresponding oximinopropanolamines 7. These compounds were studied for their potential beta-blocking properties. It was found that 7 have generally low beta 1-blocking properties. Their beta 2-blocking action varies from low to very high. Interestingly one of them (7b) has the highest beta 2 activity/beta 1 activity (343) value known to date.

Adrenergic beta-Antagonists↗
PubMed1985

New chiral and isomeric cyclopropyl ketoxime propanolamine derivatives with potent beta-adrenergic blocking properties.

The synthesis of R-(+) and S-(-) isomers of O-[3-tert-butylamino)-2-hydroxypropyl] cyclopropyl methyl ketone oxime (falintolol) is described. The syn and anti isomers of falintolol were obtained in two different ways from cyclopropyl methyl ketoxime or from falintolol. For comparison purposes, the enantiomers of the dicyclopropyl ketone oxime derivatives were also prepared. Structure-activity relationships are described.

Adrenergic beta-Antagonists↗
PubMed1992

Synthesis and beta-adrenergic antagonist activity of novel (3-oxazolinyl-1,4-dihydropyridyl) propanolamines.

A novel class of 1-(1-[4-phenyl(n-butyl or methyl)-3-(4,4-dimethyloxazolin-2-yl)-1,4- dihydropyridyl])-3-tert-butyl(or isopropyl)amino-2-propanols (7-12) were synthesized for evaluation as beta-adrenergic antagonists. Replacement of the naphthyloxy moiety of propranolol by a 1-[1-(4-n-butyl)-3-(4,4-dimethyloxazolin-2-yl)-1,4-dihydropyrid yl] group resulted in a significant decrease in cardiac beta 1-adrenergic antagonist activity which indicates that this group is not a suitable isostere for an aryloxy moiety. 1-(1-[4-n-Butyl-3-(4,4-dimethyloxazolin-2-yl)-1,4-dihydropyridy l])-3- isopropylamino-2-propanol (10) showed a modest beta 2-adrenergic antagonist selectivity for trachea (beta 2/beta 1 = 3:1).

Adrenergic beta-Antagonists↗
PubMed1991

Synthesis and beta-adrenergic antagonist activity of novel (3-cyanodihydropyridyl)propanolamines.

The synthesis and beta-adrenergic antagonist activities of 1-(1-dihydropyridyl)-3-alkylamino-2-propanols (9-16) in which the aryloxy group of aryloxypropanolamines (1) is replaced by a 1-[2-t-(n-)butyl-3-cyano-1,2-dihydropyridyl] (9-12) or 1-[6-t-(n-)butyl-3-cyano-1,6-dihydropyridyl] (13-16) moiety is described. These replacements resulted in a substantial reduction in beta 1 (atria) and beta 2 (trachea) adrenergic antagonist activities relative to the reference drug metoprolol. Structure-activity correlations indicate the relative potency order is 1,2-dihydropyridyl greater than 1,6-dihydropyridyl, n-Bu greater than t-Bu for dihydropyridyl substituents, and that this class of compounds are non-selective beta-antagonists with a beta 1/beta 2 selectivity ratio close to unity.

Adrenergic beta-Antagonists↗
PubMed1976

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↗
PubMed1977

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↗
PubMed1977

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↗
PubMed1991

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↗
PubMed1989

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↗
PubMed1989

Aminophospholipid translocase of human erythrocytes: phospholipid substrate specificity and effect of cholesterol.

The outside-inside translocation rate and transmembrane equilibrium distribution, at 37 degrees C, of 16 different amphiphilic spin-labeled phospholipids have been determined in human erythrocytes. The transmembrane distribution was assessed by bovine serum albumin extraction of the spin-labels present in the outer monolayer. Within 15 min, more than 90% of the phosphatidylserine analogue was found in the inner monolayer; the equilibrium distribution of phosphatidylethanolamine spin-label was approximately 85-90% inside, with a half-time for translocation of approximately 50 min. In contrast, phosphatidylcholine reached a distribution corresponding to approximately 30% of the labels inside with a half-time of approximately 8 h, and only traces of sphingomyelin were found in the inner monolayer after 16 h. Thus, the spin-label analogues distributed themselves like endogenous phospholipids in red cells with a spontaneous segregation between the amino lipids and the choline-containing phospholipids. Progressive methylation of the amine group of phosphatidylethanolamine resulted in a stepwise decrease of the specific transport; modification of the beta-carbon of the serine also decreased the efficiency of the rapid translocation without abolishing it. Phosphatidyl-propanolamine was not transported. Substitution of the glyceride group by a ceramide abolished the rapid outside-inside translocation even with a molecule bearing a serine head group. Also it was found that esterification of the sn-2 position of the glycerol component was necessary for a rapid translocation since lysophosphatidylserine was only slowly transported from outside to inside.(ABSTRACT TRUNCATED AT 250 WORDS)

Carrier Proteins↗
PubMed1992

Flavones. 3. Synthesis, biological activities, and conformational analysis of isoflavone derivatives and related compounds.

A series of 2-alkylisoflavone derivatives 1 was prepared with the intent to study the importance of the phenyl group (at the 3-position) of the isoflavone in imparting antihypertensive activity and the substitution effects at the 2-position of isoflavone. With the exception of the 2-isopropyl analog, the antihypertensive activity of these compounds appears to have a slow onset and long duration. None of the analogs appears better than the corresponding flavone (3) and 3-phenylflavone (2) analogs. An unsuccessful attempt to correlate the relationship between antihypertensive activity and the calculated torsional angle of C2-C3-C1'-C2' is discussed. Antiinflammatory activities of these compounds along with 7-(oxypropylamine)flavones were also evaluated and found to be not very potent. The antiinflammatory activity appears to be sensitive to steric effects of the alkyl group on the nitrogen and of substituents at the 2-position of the isoflavones, while the hydroxyl group of the propanolamine side chain is not essential.

Animals↗