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At least 19 recordsLinked to original sources
PubMed1995

Synthesis and adrenergic beta-blocking activity of ortho-, meta- and para-oxypropanolamino-substituted [(benzylideneamino)oxy]propanolamines.

The N-isopropyl- and N-t-butyl-substituted 1-[o-(3-amino-2-hydroxypropoxy)benzylideneaminoxy]-3-amino-2-propa nols (7a,b) and their meta (8a,b) and para (9a,b) isomers, in which a single aromatic ring is substituted both by the oxypropanolaminic chain of (aryloxy)propanolaminic beta-adrenergic antagonists (AOPAs) and the [(methyleneamino)oxy]propanolaminic chain of [(methyleneamino)oxy]-propanolaminic beta-blocking drugs (MAOPAs), were synthesized and assayed for their beta-adrenergic activity by functional tests on isolated preparations. Compounds 7-9 represent a new type of molecular duplication of beta-adrenergic drugs, formally deriving from the sharing of the aromatic portions of two different pharmacophoric subunits, namely the (aryloxy)propanolaminic portion of AOPAs and the [(benzylideneamino)oxy]propanolaminic portion of aryl-substituted MAOPAs. The pharmacological results showed that the beta-blocking activity of compounds 7-9 is closely related to the way in which the two subunits are linked by the aromatic nucleus: the activity decreases on passing from the ortho-compounds (7a,b) to the meta (8a,b) and then to the para (9a,b) isomers. A comparison of this activity trend with those found for series of both beta-blocking AOPAs and aryl-substituted MAOPAs seems to indicate that compounds 7-9 can be considered more as AOPAs substituted on the phenyl ring by a [(methyleneamino)oxy]propanolaminic chain rather than as aromatic MAOPAs substituted on the same phenyl moiety by an oxypropanolaminic portion.

Adrenergic beta-Antagonists↗
PubMed2005

Benzisothiazoles and beta-adrenoceptors: synthesis and pharmacological investigation of novel propanolamine and oxypropanolamine derivatives in isolated rat tissues.

In an attempt to examine the ability of benzisothiazole-based drugs to interact with beta-adrenoceptors, a series of 1,2-benzisothiazole derivatives, which were substituted with various propanolamine or oxypropanolamine side chains in the 2 or 3 position, were synthesised and tested. The pharmacological activity of these compounds at the beta-adrenoceptors was examined using isolated rat atria and small intestinal segments, which preferentially express the beta1- and beta3-adrenoceptor-mediated responses, respectively. None of these products showed any beta-adrenoceptor agonistic activity. In contrast, the 2- and 3-substituted isopropyl, tert-butyl, benzyl, and piperonyl derivatives 2a-d and 3a-d elicited surmountable inhibition of the isoprenaline-induced chronotropic effects in the atria, suggesting competitive antagonism at the beta1-recognition site. The pA2 values revealed tert-butyl 3b and the isopropyl substituted piperonyl derivatives 3a to be the most effective. Remarkably, many of the 2-substituted propanolamines were less active than the corresponding 3-substituted oxypropanolamines. With the exception of compound 3b, none of these drugs antagonised the muscle relaxant activity of isoprenaline in the intestine, suggesting no effect on the beta3-adrenoceptors. These results confirm the ability of the benzisothiazole ring to interact with the beta-adrenoceptors, and demonstrate that 2-substitution with propanolamine or 3-substitution with oxypropanolamine groups yields compounds with preferential antagonistic activity at the cardiac beta1-adrenoceptors. The degree of antagonism depends strongly on both the nature of the substituent and its position on the benzisothiazole ring.

Adrenergic beta-1 Receptor Antagonists↗
PubMed1999

Aryl propanolamines: comparison of activity at human beta3 receptors, rat beta3 receptors and rat atrial receptors mediating tachycardia.

1. The in vitro activity of four aryl propanolamines was compared to two prototypic beta3 receptor agonists, CGP 12177 and CL316243 at the human beta3 receptor, the rat beta3 receptor in the stomach fundus and receptors mediating atrial tachycardia. 2. L-739,574 was the most potent (EC50 = 9 nM) and selective agonist at the human beta3 receptor with high maximal response (74% of the maximal response to isoproterenol). 3. A phenol-biaryl ether analogue possessed modest affinity for the human beta3 receptor (EC50 = 246 nM), but was highly efficacious with a maximal response 82% of the maximal response to isoproterenol. The other derivatives were intermediate in potency with low maximal responses. 4. These agonists at the human beta3 receptor did not activate the rat beta3 receptor in the rat stomach fundus. In fact, the aryl propanolamines (10(-6) M) inhibited CL316243-induced activation of the rat beta3 receptor. Thus, agonist activity at the human beta3 receptor translated into antagonist activity at the rat beta3 receptor. 5. L739,574 and the phenol biaryl ether increased heart rate via beta1 receptors. 6. Although CGP12177 produced atrial tachycardia, neither the indole sulphonamide nor biphenyl biaryl ether did, although both had high affinity for the human beta3 receptor. Thus, the atrial tachycardic receptor was not identical to the human beta3 receptor. 7. These studies (a) characterized four aryl propanolamines with high affinity at the human beta3 receptor, (b) found that they were antagonists at the rat beta3 receptor, an observation with profound implications for in vivo rat data, and (c) established that the rodent atrial non-beta1, beta2 or beta3 tachycardic receptor was also unrelated to the human beta3 receptor.

Adrenergic beta-Agonists↗
PubMed2005

Substituted propanolamines and alkylamines derived from fluoxetine as potent appetite suppressants.

A series of propanolamine and alkylamine analogues of fluoxetine (7-26, 28-31) were synthesized and assessed for their anorexigenic and antidepressant activities. Effect of various substituents at C-4 aryl position of fluoxetine has also been studied. Most of the propanolamine analogues (7-13, 16-26) displayed significant anorexigenic activity but interestingly they were devoid of antidepressant activity whereas anorexigenic as well as antidepressant activity was retained in the alkylamine series (28-31). Compounds 10 and 26 emerged as the most active compound and anorexigenic activity was better (83.67% and 82.45%) compared to fluoxetine (81.25%).

Animals↗
PubMed1981

beta-Adrenergic blocking agents. alpha- and gamma-methyl(aryloxy)propanolamines.

A series of gamma-methyl- (5) and alpha-methyl(aryloxy)propanolamines (6) were synthesized and evaluated for beta-adrenergic blocking action. The binding constant (KD) was determined for compounds 5a-j on cultured C6-2B astrocytoma cells. Compounds 5a-j and 6a-e were evaluated for beta 1-antagonist action on guinea pig atria and beta 2-antagonist action on guinea pig tracheal strips. Several gamma-methyl(aryloxy)propanolamines showed affinity for beta receptors and a possible preference for beta 2 receptors.

Adrenergic beta-Antagonists↗
PubMed1983

beta 1-selective adrenoceptor antagonists. 1. Synthesis and beta-adrenergic blocking activity of a series of binary (aryloxy)propanolamines.

A series of binary (aryloxy)propanolamines has been prepared and examined in vitro and in vivo for beta-adrenoreceptor blocking activity. These symmetrical compounds consist of two (S)-(phenyloxy)propanolamine pharmacophores coupled through alkylenedioxy or poly(oxyethylenedioxy) linking units of varying lengths. Examples of such binary compounds linked through the 2,2', 3,3', and 4,4' positions in the aromatic rings of the pharmacophores have been prepared. In vitro and in vivo test data indicate that the 2,2' compounds tend to be selective beta 2-adrenergic blocking agents, the 4,4' binaries tend to be selective beta 1-blocking agents, and those compounds with 3,3' linkages exhibit intermediate selectivities. One of the 4,4'-linked binary compounds, 4s, exhibited potent, cardioselective beta-blockade in vivo, which was of short duration and was accompanied by a prolonged tachycardia.

Adrenergic beta-Antagonists↗
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↗
PubMed1996

Binding of arylpiperazines, (aryloxy)propanolamines, and tetrahydropyridylindoles to the 5-HT1A receptor: contribution of the molecular lipophilicity potential to three-dimensional quantitative structure-affinity relationship models.

A set of 280 5-HT1A receptor ligands were selected from available literature data according to predefined criteria and subjected to three-dimensional quantitative structure-affinity relationship analysis using comparative molecular field analysis. No model was obtained for serotonin analogues (19 compounds) and aminotetralins (60 compounds), despite a variety of alignment hypotheses being tried. In contrast, the steric, electrostatic, and lipophilicity fields alone and in combination yielded informative models for arylpiperazines (101 training compounds and 12 test compounds), (aryloxy)propanolamines (30 training compounds and four test compounds), and tetrahydropyridylindoles (54 training compounds) taken separately (models A, B, and C). Arylpiperazines and (aryloxy)propanolamines were then combined successfully to yield reasonably good models for 131 compounds (model D). In a last step, the three chemical classes (185 compounds) were combined, again successfully (model E). This stepwise procedure not only ascertains self-consistency in alignments but it also allows statistical signals (i.e., favorable or unfavorable regions around molecules) to emerge which cannot exist in a single chemical class. The models so obtained reveal a number of interaction sites between ligands and the 5-HT1A receptor, and extend the information gathered from a model based on homology modeling.

Indoles↗
PubMedDate not supplied

Synthesis and beta-adrenergic activity of a series of 3-(substituted-benzylideneaminoxy)propanolamine derivatives.

In an attempt to change the beta-adrenergic properties of completely aliphatic 3-(methyleneaminoxy)propanolamine derivatives, from antagonist to agonist, while still retaining the beta 2-selectivity, we described, in a previous paper, the synthesis of a series of such derivatives possessing a hydroxy or methoxy group linked to the aliphatic substituent present on the oximic carbon. However, pharmacological tests indicated that these compounds maintain the competitive antagonism on beta receptors. In this paper, the synthesis and the results of functional tests on isolated preparations are reported for a new series of 3-(substituted-benzylideneaminoxy)propanolamine derivatives in which either the hydroxy or the methoxy group is linked to a phenyl ring present on the oximic carbon. The results obtained are then discussed, taking into account the conformational and reactivity properties of these compounds, determined by means of theoretical calculations.

Adrenergic beta-1 Receptor Agonists↗
PubMed1994

Synthesis and beta-adrenergic activity of new completely aliphatic 3-(methyleneaminoxy)propanolamine derivatives.

In a previous paper, it had been found that completely aliphatic 3-(methylene aminoxy)propanolamine derivatives showed a good beta-blocking adrenergic activity directed prevalently towards beta 2-tracheal receptors. In an attempt to change the beta-adrenergic properties of these compounds from antagonist to agonist, while still retaining the beta 2-selectivity, a series of new completely aliphatic 3-(methyleneaminoxy)propanolamine derivatives were designed in which either a hydroxylic or a methoxylic group was present on the aliphatic portion linked to the oximic carbon. The synthesis of the new compounds and their beta-adrenergic activity, evaluated by means of functional tests on isolated preparations, are described and discussed; the results obtained are then rationalised on the basis of their conformational and reactivity characteristics, determined by means of theoretical methods.

Adrenergic Agents↗
PubMed2005

Persistence and biodegradation of monoethanolamine and 2-propanolamine at an abandoned industrial site.

Soil and groundwater samples were collected at the site of a former chemical processing plant in areas impacted by accidental releases of MEA (monoethanolamine) and IPA (2-propanolamine or isopropanolamine). Although their use had ceased ca. 10 years before sample collection, soils collected at contamination sites had MEA concentrations ranging from ca. 400 to 3000 mg/kg and IPA concentrations from ca. 30 to 120 mg/kg. Even though alkanolamines are miscible in water, transport to groundwater was slow, apparently because they are present in soil as bound cations. Only one groundwater sample (near the most highly contaminated soil)from wells directly adjacentto and down-gradient from the contaminated soils had detectable MEA, and none had detectable IPA. However, ammonia was found in the soil samples collected in the MEA-contaminated areas (ca. 500-1400 mg/kg) and the groundwater (80-120 mg/L), as would be consistent with bacterial degradation of MEA to ammonia, followed by transport of ammonia into the groundwater. Counts for bacteria capable of using MEA or IPA as a sole carbon source were ca. 5 x 106 and 1 x 106 (respectively) per gram in uncontaminated site soil, but no such organisms were found in highly contaminated soils. Similarly, bacterial degradation of MEA in slurries of highly contaminated soils was slow, with ca. 8-20 days required for half of the initial concentrations of MEA to be degraded at 20 degrees C and 30-60 days at 10 degrees C. In contrast, bacterial degradation studies using uncontaminated site soils spiked with ca. 1300 mg/L either MEA or IPA showed very rapid degradation of both compounds,with more than 99% degradation occurring in less than 3 days with quantitative conversion to ammonia, followed by slower conversion to nitrite and nitrate. The results obtained in the site soils, the groundwater samples, and from the biodegradation studies demonstrate that MEA and IPA can persist for decades on soil at high (hundreds of mg/kg) concentrations without significant migration into groundwater, despite the fact that they are miscible in water. Since MEA and IPA exist primarily as cations at the pH of site soils, their persistence apparently results from strong binding to soil, as well as inhibition of natural bioremediation in highly contaminated field soils.

Ammonia↗
PubMed1993

o-Chlorobenzenesulfonamidic derivatives of (aryloxy)propanolamines as beta-blocking/diuretic agents.

A series of compounds 1b-f, 2b-f, and 3b-f having an o-chlorobenzenesulfonamidic diuretic moiety variously linked to the nitrogen side chain of the beta-blocking (aryloxy)propanolamine pharmacophore were prepared and tested for their beta 1-adrenoceptor affinity. For all the active compounds, beta-blocking and diuretic activities were investigated in rats; the structure--activity relationships are discussed. Some of the compounds displayed varying levels of both properties and among these, compounds 1c and 2c have been chosen for further development.

Adrenergic beta-Antagonists↗
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↗
PubMed1986

[p-[(Thienylcarbonyl)amino]phenoxy]propanolamines derivatives as diuretic and beta-adrenergic receptor blocking agents.

The synthesis of [[(thienylcarbonyl)amino]phenoxy]propanolamines and their beta-adrenergic blocking and diuretic activity are described. Structure-activity relationships demonstrated that ortho substitution of the phenoxy ring with an hydrogen or an ester function leads to compounds possessing both activities. Ethyl 2-[3-[(1,1-dimethylethyl) amino]-2-hydroxypropoxy]-5-[(2-thienylcarbonyl)amino]benzoate (3d) was selected as the most active compound for further investigation.

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↗
PubMed1982

Ultra-short-acting beta-adrenergic receptor blocking agents. 1. (Aryloxy)propanolamines containing esters in the nitrogen substituent.

In an attempt to produce short-acting beta-adrenergic receptor blocking agents, we prepared several (aryloxy)propanolamines with ester functions incorporated into the nitrogen substituent. Many of these compounds exhibited a short duration of blocking activity after their continuous intravenous infusion for 40 min. However, their durations were found to increase considerably upon longer intravenous infusion.

Adrenergic beta-Antagonists↗