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PubMed2002

Structure-activity relationship studies of phenoxypropanolamine derivatives for beta 3-adrenergic activity.

In this study, some compounds of phenoxypropanolamine (SWR-0342SA) derivatives were found to possess beta 3-adrenoceptor (beta 3-AR) agonistic activity. Addition and deletion of the substituents on phenoxyacetate, chain length variation between two aromatic rings, conversion of phenoxypropanolamine to phenylethanolamine, insertion of double bonds and another ether group in the side chain between two phenyl rings in SWR-0342SA derivatives resulted in novel phenoxypropanolamine and phenylethanolamine compounds. This study was performed to evaluate the structural modification of the parent SWR-0342SA and their effects on the binding affinities as well as functional activities of these derivatives using COS-7 cells and CHO cells expressing human beta 1, beta 2, beta 3-AR and only beta 3-AR respectively. Compounds SWR-0342SA, SWR-0339SA (S-enantiomer with trans-ethylidene group), SWR-0315NA (non-isomeric with racemic ethylidene group and sodium salt), and SWR-0334NA (non-isomeric with trans-ethylidene group and sodium salt), all belonging to phenoxypropanolamine group, were found to have high binding and functional activities and were supposed to be potent beta 3-AR agonists. Since many of the phenoxypropanolamine compounds acts as antagonists to beta 1- and beta 2-ARs, these derivatives have also been evaluated for their affinity to beta 1- and beta 2-ARs. The pKi values of these derivatives to beta-AR subtypes were also compared. These compounds show little selectivities towards beta 3-AR subtypes.

Acetates↗
PubMed2002

CoMFA analysis of the human beta(1)-adrenoceptor binding affinity of a series of phenoxypropanolamines.

A series of 36 phenoxypropanolamines was examined to determine the structure--activity relationships of beta-adrenoceptor (beta-AR) antagonists for the human beta(1)-AR. The binding affinities of all the compounds were determined for human beta(1)-ARs expressed in Chinese hamster ovary cells and the antagonist potency for rat atrial beta(1)-ARs was determined for 32 of these compounds for comparative purposes. The compounds, based upon a phenoxypropanolamine core structure with various meta-, ortho-, para- and amine-substituents, displayed binding affinities (pK(i)) for the human beta(1)-AR ranging from 5.49 to 9.35. Antagonist potencies (pA(2)) in the rat ranged from 5.52 to 9.56 and correlated with the human binding affinities (r(2)=0.86). Twenty-six compounds were used as the training set for comparative molecular field analysis (CoMFA) of antagonist binding affinity at the human beta(1)-AR and also of antagonist potency for rat atrial beta(1)-ARs. The CoMFA models were derived using both the CoMFA electrostatic and steric field parameters. The initial human beta(1)-AR model (n=26, q(2)=0.59, ONC=6, SE(CV)=0.70, r(2)=0.98, SE(non-CV)=0.16, F(6,19)=148) predicted the binding affinities of seven out of ten test compounds, not included in the training set, with residual pK(i) values less-than-or-equal0.50. The final human beta(1)-AR model (n=36, q(2)=0.66, ONC=5, SE(CV)=0.61, r(2)=0.95, SE(non-CV)=0.24, F(5,30)=107), consisting of the training set plus the test set of compounds, may prove useful in the design of new phenoxypropanolamine type beta(1)-AR antagonists. The initial rat beta(1)-AR model (n=26, q(2)=0.42, ONC=6, SE(CV)=0.76, r(2)=0.94, SE(non-CV)=0.25, F(6,19)=47) predicted the affinities of five out of six test compounds with residual pA(2) values less-than-or-equal0.50. The final rat beta(1)-AR model (i.e. training set plus test set of compounds) (n=32, q(2)=0.38, ONC=5, SE(CV)=0.69, r(2)=0.93, SE(non-CV)=0.24, F(5,26)=67) in particular has a low q(2) value, indicating that, at least for the rat, the biologically active phenoxypropanolamine conformation may be quite different to the low energy extended conformation chosen for this CoMFA study.

Adrenergic beta-1 Receptor Antagonists↗
PubMed2005

Synthesis of 4-(1-oxo-isoindoline) and 4-(5,6-dimethoxy-1-oxo-isoindoline)-substituted phenoxypropanolamines and their beta1-, beta2-adrenergic receptor binding studies.

Phenoxypropanolamines with 1-oxo-isoindoline and 5,6-dimethoxy-1-oxo-isoindoline groups at the para position were synthesized. beta1, beta2-Adrenergic receptor binding affinities for the synthesized compounds were tested and compared with propranolol and atenolol. It was found that the incorporation of para-amidic functionality within the 1-oxo-isoindoline ring and 5,6-dimethoxy-1-oxo-isoindoline ring system led to a high degree of cardioselectivity in the phenoxypropanolamines. Two of the compounds and possessed beta1-adrenergic receptor affinity comparable with that of atenolol and both showed a better cardioselectivity than atenolol. Both and are undergoing further pharmacological evaluation.

Adrenergic beta-1 Receptor Antagonists↗
PubMed2003

Binding and functional affinity of some newly synthesized phenethylamine and phenoxypropanolamine derivatives for their agonistic activity at recombinant human beta3-adrenoceptor.

Beta(3)-adrenoceptor is the predominant beta-adrenoceptor in adipocytes and has drawn much attention during the investigation for anti-obesity and antidiabetes therapeutics. Thirteen new compounds have been evaluated for their potencies and efficacies as beta(3)-adrenoceptor agonists on human beta(3)-adrenoceptor expressed in COS-7 and Chinese hamster ovary (CHO) cells using radioligand binding assay and cyclic AMP (cAMP) accumulation assay. Phenoxypropanolamine derivatives, SWR-0334NA (([E)-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene-3-yl] phenoxy]acetic acid sodium salt), SWR-0335SA ((E)-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene-3-yl] phenoxy] acetic acid ethanedioic acid), SWR-0342SA (S-(Z)-[4-[[1-[2-[(2-hydroxy-3-phenoxypropyl)]amino] ethyl]-1-propenyl]phenoxy] acetic acid ethanedioic acid), SWR-0348SA-SITA ((E)-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-hexene-3-yl] phenoxy]acetic acid ethanedioic acid) and SWR-0361SA ((E)-N-methyl[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene-3-yl]phenoxy]acetoamide ethanedioic acid) showed higher agonistic activity for the beta(3)-adrenoceptor. Among the compounds tested, SWR0334NA exhibited full agonist activity (%E(max) = 100.26) despite its lower binding affinity (pK(I) = 6.11). Compounds SWR-0338SA ((E)-[4-[5-[(2-phenyl-2-hydroxyethyl)amino]-2-pentene-3-yl] phenoxy]acetic acid ethanedioic acid), SWR-0339SA (S-(E)-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene-3-yl] phenoxy] acetic acid ethanedioic acid), SWR-0345HA ((E)-2-methyl-3-[4-[2-(2-phenyl-2-hydroxyethyl-amino)ethoxy] phenyl]-2-propenoic acid ethyl ester hydrochloride), SWR-0358SA ((E)-(2-methoxyethyl)-[4-[5-[(3-phenoxy-2-hydroxypropyl) amino]-2-pentene-3-yl]phenoxy]acetoamide ethanedioic acid) and SWR-0362SA ((E)-1-[[[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene-3-yl]phenoxy]acetyl]carbonyl]piperidine ethanedioic acid) had moderate agonistic activity and were phenethylamine and phenoxypropanolamine derivatives. Compounds SWR-0065HA ([4-[2-[3-[[(3,4-dihydro-4-oxo-[1,2,4]-triazino(4,5-a)indol)-lyl]oxy]-2-hydroxypropylamino]ethoxy]phenyl]acetic acid methyl ester hydrochloride), SWR-0098NA ((E)-[4-[3-[(2-phenyl-2-hydroxyethyl)amino]-1-butenyl] phenoxy]acetic acid sodium salt) and SWR-0302HA ([4-[[4-[2-(3-chlorophenoxy-2-hydroxypropyl)amino]-E-2-butenyl]oxy]phenoxy]acetic acid hydrochloride) had very low binding affinity towards beta(3)-adrenoceptors and they did not induce cAMP accumulation. We concluded that compounds SWR-0334NA, SWR-0335SA, SWR-0342SA, SWR-0348SA-SITA and SWR-0361SA were potential agonists of human beta(3)-adrenoceptor. Further investigation on their selectivity towards beta(3)-adrenoceptor could be useful for the exploration of the physiological properties of the beta(3)-adrenoceptor.

Adipocytes↗
PubMed2005

Comparison of the binding affinity of some newly synthesized phenylethanolamine and phenoxypropanolamine compounds at recombinant human beta- and alpha1-adrenoceptor subtypes.

We evaluated six new compounds, SWR-0065HA ([4-[2-[3-[[(3,4-dihydro-4-oxo-[1,2,4]-triazino(4,5-a)indol)-lyl]oxy]-2-hydroxypropylamino]ethoxy]phenyl]acetic acid methyl ester hydrochloride), SWR-0098NA ((R*R*-UE)-(E)-[4-[3-[(2-phenyl-2-hydroxyethyl)amino]-1-butenyl]phenoxy]acetic acid sodium salt), SWR-0315NA ((E, Z)-[4[[1-[2-[(3-phenoxy-2-hydroxy propyl)]amino]ethyl]-1-propenyl]phenoxy]acetic acid sodium), SWR-0338SA ((E)-[4-[5-[(2-phenyl-2-hydroxyethyl)amino]-2-pentene-3-yl]phenoxy] acetic acid ethanedioic acid), SWR-0342SA ((S)-(Z)-[4-[[1-[2-[(2-hydroxy-3-phenoxypropyl)]amino] ethyl]-1-propenyl]phenoxy]acetic acid ethanedioic acid) and SWR-0345HA ((E)-2-methyl-3-[4-[2-(2-phenyl-2-hydroxyethylamino)ethoxy]phenyl]-2-propenoic acid ethyl ester hydrochloride) for their potencies as selective ligands at human beta-adrenoceptors expressed in COS-7 cells and compared the binding affinities for human alpha(1)-adrenoceptors expressed in Chinese hamster ovary (CHO) cells using a radioligand-binding assay. Phenoxypropanolamine derivatives SWR-0315NA and SWR-0342SA showed higher binding affinities for beta-adrenoceptor subtypes; SWR-0065HA, however, showed a higher affinity for only beta-adrenoceptors, accounting for 3-fold and 6-fold selectivity against beta(1)- and beta(3)-adrenoceptors. Compounds SWR-0315NA and SWR-0342SA did not show any binding selectivity for any of the subtypes. However, functionally these two compounds are selective for beta(3)-adrenoceptors. Among the phenylethanolamine derivatives, SWR-0338SA and SWR-0345HA showed 9-fold and 16-fold higher binding selectivity for beta(3)-adrenoceptors against beta(1)-adrenoceptors, respectively, whereas they both showed a 7-fold higher binding selectivity for beta(3)-adrenoceptors against beta(2)-adrenoceptors. SWR-0098NA did not show any significant binding affinity for any of the beta-adrenoceptor subtypes. These compounds, except for SWR-0098NA, were not found to possess any significant binding affinity for alpha(1)-adrenoceptor subtypes over that for beta-adrenoceptor subtypes. However, SWR-0098NA has about a 3-fold to 22-fold higher binding selectivity for alpha(1)-adrenoceptor subtypes against beta-adrenoceptor subtypes, making it difficult for use in a beta-adrenoceptor receptor study. Compounds SWR-0315NA and SWR-0342SA have similar binding potency for alpha(1)-adrenoceptors as adrenaline (epinephrine), proving the finding of this manuscript that this phenoxypropanolamine group of beta-adrenoceptor ligands could also be used as alpha(1)-adrenoceptor ligands. Functional assays have to be performed to confirm their agonistic activity.

Adrenergic beta-Agonists↗
PubMed1976

[Structure-activity relationships of halogenated phenylethanolamine and phenoxypropanolamine].

12 compounds from the series of halogenated phenylethanolamines and phenoxypropanolamines were tested at the isolated rabbit jejunum, and the pD2-and pA2-values were determined. All the substances act beta-adrenolytically. Except for 3,4-dichloronoradrenaline, which stimulates the alpha-receptors, all the compounds still have pronounced beta-mimetic effects. The 2,5-dihalogenated phenylethanolamines and phenoxypropanolamines block the beta-receptors at lower concentrations than 2,4-dihalogen derivatives. The weakest beta-adrenolytic effects at the intestine were found with compounds halogenated at the 3,4-position.

Adrenergic beta-Antagonists↗
PubMed1985

Effects of para-substituted beta-adrenoceptor blocking agents and methyl-substituted phenoxypropanolamine derivatives on maximum upstroke velocity of action potential in guinea-pig papillary muscles.

The effects of atenolol (2-5 mmol/l), sotalol (1-2 mmol/l) and pamatolol (0.1-1 mmol/l), together with N-tertiary butyl phenoxypropanolamines with o-methyl (D-2T: 50-100 mumol/l) m-methyl (D-3T: 50-100 mumol/l) and p-methyl (D-4T: 100-200 mumol/l) group as well as with o,p-methyl groups (D-24T) (50-100 mumol/l) on action potentials (APs) were investigated in isolated guinea-pig papillary muscles. All the drugs in these concentrations produced a concentration-dependent reduction of the maximum upstroke velocity (Vmax). The reduction of Vmax in premature APs induced by stimuli interpolated between the basic driving rate of 0.25, 0.1 or 0.027 Hz decayed exponentially during diastolic intervals. The time constants of these decay processes tau for atenolol, pamatolol and sotalol ranged between 260-541 ms, those for D-3T and D-4T between 655-1,166 ms, and D-2T and D-24T between 1,565-1,931 ms. A drug which provided larger tau values caused the reduction of Vmax in a wider range of the frequency.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1987

The membrane stabilizing activity of beta-adrenoceptor ligands. Quantitative evaluation of the interaction of phenoxypropanolamines with the [3H]batrachotoxinin A 20-alpha-benzoate binding site on voltage-sensitive sodium channels in rat brain.

The interaction of 12 phenoxypropanolamines, all ligands with high affinity towards beta-adrenoceptors, with the [3H]batrachotoxinin A 20-alpha-benzoate ([3H]BTX-B) binding site on voltage-sensitive sodium channels in a rat brain synaptosomal preparation, was studied as a measure for local anaesthetic activity. All derivatives are capable of displacing [3H]BTX-B from its specific binding site, penbutolol displaying the highest affinity. Multiple regression analyses were performed, correlating biological activity (pKi values) with physicochemical parameters. Lipophilicity is of prime importance in the established regression equations, but steric factors are relevant as well. Comparisons were made with analogous equations relating beta 1- and beta 2-adrenoceptor affinity with physicochemical parameters, leading to the conclusion that "cardioselective" beta-adrenoceptor ligands appear to have fewer membrane stabilizing properties.

Adrenergic beta-Agonists↗
PubMed1990

Genetic toxicity of a pharmacologically active group of ortho-(arylalkynyl)phenoxypropanolamines.

A series of ortho-(arylalkynyl)phenoxypropanolamines with antihypertensive activity in laboratory animals was screened in vitro for mutagenicity using the Ames test and the mouse lymphoma assay, and for DNA damaging potential in the primary rat hepatocyte/DNA repair assay. Those compounds with a dialkylamino group on the para position of the arylalkynyl function were shown to be genotoxic in both mutagenicity assays when tested in the presence of an Aroclor 1254-induced rat liver S-9 mix. They were also active in the DNA repair assay. Removal of the para-dialkylamino group or changing the position of this group on the aryl ring eliminated the genotoxic effect in these test systems. This collaborative effort between chemists, pharmacologists, and toxicologists successfully identified the structural feature responsible for the genotoxic activity and indicated structural alterations that would yield a pharmacologically active compound with no genotoxicity in these in vitro assays.

Animals↗
PubMed1985

Quantitative evaluation of the beta 2-adrenoceptor affinity of phenoxypropanolamines and phenylethanolamines.

The influence of the aromatic moiety of beta-adrenoceptor ligands on the affinity for the beta 2-adrenoceptor has been studied. Three classes of ligands have been examined, viz. N-isopropyl- and N-tert-butylphenylethanolamines and N-isopropylphenoxypropanolamines. Computer-assisted analysis of the inhibition by any of these ligands of the specific (-)-[3H]dihydroalprenolol binding to the beta 2-adrenoceptors of a bovine skeletal muscle preparation in the presence of GppNHp (10(-4) M) yielded the affinities of these ligands at pH 7.5. The obtained values were adjusted for the amounts of cations present at this pH value. A significant correlation was found between the calculated lipophilicities and the experimentally determined affinities in the three classes. Furthermore, steric factors seem to play an important role, as these correlations were improved by the introduction of steric parameters for the aromatic substituents in the regression analyses. From the established equations it is concluded that the phenoxypropanolamine derivatives bind to the beta 2-adrenoceptor in a way different from that of the ligands in both ethanolamine classes.

Animals↗
PubMed1983

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↗
PubMed1984

Beta 1-selective adrenoceptor antagonists. 3. 4-Azolyl-linked phenoxypropanolamines.

A series of 4-substituted phenoxypropanolamines has been prepared and examined for beta-adrenoceptor activity. The 4-substituents, di- and triazole ring systems connected to the phenoxy ring by different length chains, were chosen as a means of introducing cardioselectivity. This has been achieved, especially in the 1-[4-[(4-chloropyrazol-1-yl)methoxy] phenoxy]-3-(isopropylamino)-2-propanol (11), the 4-[(2H-1,2,3-triazol-2-yl)methoxy] analogue (21), and the 4-[2-(2H-1,2,3-triazol-2-yl)ethoxy] analogue (22), which show potent beta 1-blockade with selectivity ratios in excess of 100:1. Structure-activity relationships are discussed, and the optimum position of the heteroatom in the 4-substituent is defined.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Agonistic and antagonistic actions of 3,4-dihydroxy-substituted phenoxypropanolamines in guinea-pig atria and trachea.

1. Racemic mixtures of noradrenaline, adrenaline, isoprenaline, N-t-butylnor-adrenaline and their corresponding derivatives containing an oxymethylene (OM) link between the phenyl ring and ethanolamine side-chain have been tested for their effects on beta-adrenoceptors in isolated guinea-pig atrial and tracheal preparations. 2. In atrial and in spontaneously contracted tracheal preparations both the parent catecholamines and their corresponding OM-derivatives had a similar order of potency as beta-receptor agonists. 3. In carbachol-stimulated tracheal preparations the OM-derivatives were shown to have partial agonistic actions. 4. As in other phenylethanolamines and phenoxypropanolamines, both the agonistic and antagonistic potency of the OM-derivatives increased with increasing amine substitution.

Airway Resistance↗
PubMed1987

[The anxiolytic action of phenoxypropanolamine derivatives in comparison with propranolol, diazepam and placebo].

The hypothesis that the phenoxypropanolamine derivative CGP 361 A possesses anxiolytic activity was examined in 80 female healthy volunteers. Each volunteer received the treatment under double-blind conditions as part of a 1-way analysis of variance design. The medication factor had 4 levels (CGP 361 A, propranolol, diazepam and placebo). Stress was induced by asking subjects to deliver a free speech in front of a video camera. The anxiety was measured using adjectives list, state-trait-anxiety inventory and visual analogue scales. The physiological equivalents observed were pulse rate and skin resistance. The results support the hypothesis that a single dose of 10 mg CGP 361 A has a higher anxiolytic effect than 10 mg propranolol, 5 mg diazepam and placebo, with the peripheral beta-blocking effects (established by pulse rate) being no stronger than with propranolol. No subjective or objective sedation has been determined under the different drug conditions.

Adult↗
PubMed1995

Relationships between conformational behaviour and binding affinity towards beta 1 and beta 2 adrenoceptors of some chiral phenoxypropanolamines with bulky N-substituents.

The optical isomers of a series of phenoxypropanolamine compounds with N-substituents bulkier than isopropyl have been synthesized, and their binding affinity towards beta 1 and beta 2-adrenoceptors has been determined. A computational study, including a Molecular Dynamics (MD) simulation and quenching in water and a GRID analysis provided some useful suggestions for possible interpretation patterns for the different affinity exhibited by the compounds studied.

Computer Simulation↗
PubMed1988

Interactions of isamoltane (CGP 361A), an anxiolytic phenoxypropanolamine derivative, with 5-HT1 receptor subtypes in the rat brain.

Isamoltane (CGP 361A; (1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propanol hydrochloride), a beta-adrenoceptor ligand (IC50 = 8.4 nmol/l) which has reported activity as an anxiolytic in man was found to be a reasonably active inhibitor of the binding of [125I]ICYP to 5-HT1B recognition sites in rat brain membranes with 27-fold selectivity (IC50 = 39 nmol/l) as compared to the inhibition of binding of [3H]8-OH-DPAT to 5-HT1A receptors (IC50 = 1070 nmol/l). This selectivity was considerably greater than that observed for other beta-adrenoceptor ligands including propranolol (5-HT1A/5-HT1B ratio = 2), oxpenolol (3.5) and cyanopindolol (8.7). The 5-HT1B activity of the compound resided in the (-)-enantiomer. (-)-Isamoltane had weak activity (IC50 3-10 mumol/l) at 5-HT2 and alpha 1-adrenoceptors. The compound was devoid of activity at a number of other central neurotransmitter recognition sites including the 5-HT1C site. Isamoltane increased the electrically evoked release of [3H]5-HT from prelabeled rat cortical slices in a manner similar to that of cyanopindolol. While both compounds were similar in potency to methiothepin, they had lower efficacy. Oxprenolol was less potent that both isamoltane and cyanopindolol while propranolol was essentially inactive. The effects of the compounds on 5-HT release appeared to be correlated with their 5-HT1B rather than 5-HT1A activity. In vivo, isamoltane increased 5-HTP accumulation in rat cortex following central decarboxylase inhibition at doses of 1 and 3 mg/kg i.p. At higher doses this effect was gradually diminished. Similar, but less clearcut results were obtained with cyanopindolol and oxprenolol, but propranolol was ineffective. No changes in brain tryptophan levels were associated with the isamoltane-evoked changes in brain 5-HTP levels. In reserpinized animals, isamoltane reduced 5-HTP accumulation even at doses which enhanced accumulation of this metabolite when given alone. The effects of the putative 5-HT1B agonist, m-trifluoromethylphenylpiperazine (TFMPP), the mixed 5-HT autoreceptor agonist/antagonist/beta-adrenoceptor antagonist, pindolol, the 5-HT uptake inhibitor, CGP 6085A and the MAO-A inhibitor, brofaromine, were not antagonized by pretreatment with isamoltane. The possibility that isamoltane and the other beta-adrenoceptor antagonists are antagonists at 5-HT1B receptors and that their effect on 5-HT synthesis in vivo is the net result of their agonist/antagonist effects at 5-HT1A and 5-HT1B receptors is discussed in relation to the potential mechanism of the anxiolytic activity of isamoltane.

5-Hydroxytryptophan↗