Alteration of relative affinities toward myocardial and vascular .beta. adrenoceptors induced by side-chain substitution of aryloxypropanolamines

Shtacher, Gad; Rubinstein, Rachel; Somani, Pitambar

doi:10.1021/jm00205a016

Cited by 21 publications

(8 citation statements)

References 12 publications

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“…In previously studied catecholamines (Dowd et al, 1977), the inclusion of an oxymethylene group produced a small degree of #,-receptor selectivity; the oxymethylene derivative of isoprenaline was the most active compound in this respect, being some five times more active as a ,1than as a fl2-receptor agonist. In fl-receptor antagonists based on a phenoxypropanolamine nucleus, homoveratryl as opposed to isopropyl or N-t-butyl amine substitution, produces little change in antagonistic potency at ,B,-receptors while causing a marked diminution of activity at #2-receptor sites: hence the compounds show #,B-receptor selective antagonistic actions (Hoefle, Hastings, Meyer, Corey, Holmes & Stratton, 1975;Leclerc, Mann, Wermuth, Bieth & Schwartz, 1977;Shtacher, Rubenstein & Somani, 1978).…”

Section: Discussionmentioning

confidence: 99%

In vitro ACTIVITY OF RO363, A β₁‐ADRENOCEPTOR SELECTIVE AGONIST

Iakovidis¹,

Malta²,

McPherson³

et al. 1980

British J Pharmacology

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1 The #-adrenoceptor stimulant effects of R0363 and (-)-isoprenaline have been compared in a variety of isolated tissue preparations. 2 R0363 is approximately half as potent as (-)-isoprenaline in tissues where actions are due to #l,-receptor activation (guinea-pig atrial and ileal preparations and ventricular strips from the rabbit, rat and guinea-pig).3 In uterine and lung strip preparations from the guinea-pig, where responses are due to f32-receptor stimulation, R0363 is 100 to 350 times less active than (--isoprenaline and has a low intrinsic activity. 4 In spontaneously contracted tracheal preparations from the guinea-pig, R0363 is a full agonist and is approximately half as potent as (--isoprenaline. These effects of R0363 are due to the activation of a population of #l-receptors in the tissue since R0363 and (--isoprenaline have the same relative potencies in trachea, cardiac and ileal preparations. In addition the KB values for practolol are similar in all these preparations when R0363 is used as the agonist. 5 The results show that R0363 is a potent and highly selective #,-receptor agonist.

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Section: Discussionmentioning

confidence: 99%

In vitro ACTIVITY OF RO363, A β₁‐ADRENOCEPTOR SELECTIVE AGONIST

Iakovidis¹,

Malta²,

McPherson³

et al. 1980

British J Pharmacology

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“…Assignments of relative configurations to acyclic diastereoisomers is often based on the magnitude of the vicinal coupling constant J. In general J erythro is greater than J threo unless intramolecular hydrogen bonding exists where this factor may contribute more to conformational preferences than simple steric considerations in which case J threo would be greater than J erythro (5,(8)(9)(10).…”

Section: --mentioning

confidence: 99%

“…The reaction of Z and Eoxiranes with nucleophiles as amines give rise to the respective threo (1R,2R/lS,2S) and erythro (1R,2S/lS,2R) 0-aminoalcohol diastereoisomers (8)(9)(10). Thus, reaction of stereoisomers 8a and 9a (60:40 mixture) with piperidine at 8 0 ' for 8h gave a mixture of threo-(lOa) and erythro-l-hydroxy-l-(l-oxido-2-pyridinyl) 2-(l-piperidino)propane (lla), respectively, in a ratio of 6 0 4 (75.8%).…”

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confidence: 99%

Synthesis and reactions of 1‐[1‐oxido‐2‐(3,4)‐pyridinyl]‐2‐methyloxiranes with nitrogen nucleophiles

Avasthi

Knaus

1981

Journal of Heterocyclic Chem

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Reaction of 2(3,4)‐pyridinecarboxaldehydes (5) with ethylidenetriphenylphosphorane afford a mixture of stereoisomers Z‐(6) and E‐1‐[2(3,4)‐pyridinyl]‐1‐propenes (7). m‐Chloroperbenzoic acid oxidation of 6 and 7 yields a 60:40 mixture of Z‐(8) and E‐1‐[1‐oxido‐2(3,4)‐pyridinyl]‐2‐methyloxiranes (9). The regiospecific reaction of Z‐isomers 8a‐c with cyclic amines as piperidine give rise to threo‐1‐hydroxy‐1‐[1‐oxido‐2(3,4)‐pyridinyl]‐2‐(1‐piperidino)propanes (10) while the E‐isomer 9a yields erythro‐11. On tho other hand, the E‐isomers 9b and 9c having 1‐oxido‐3(4)‐pyridinyl substituents afford erythro‐12 resulting from attack by piperidine at C‐1 of the oxirane. Reductive deoxygenation using 10% palladium on charcoal and hydrogen gas effectively removed the N‐oxide substituent from the threo‐10 and erythro‐11 β‐aminoalcohols. Dilute solution ir spectroscopy indicated the existance of strong intramolecular hydrogen bonding in the β‐aminoalcohols 10 and 11. The assignment of relative configuration of diastereoisomers 10 and 11 was based on the magnitude of the vicinal coupling constant J where J threo is greater than J erythro.

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“…A striking contrast is provided when the 4-hydroxyphenethyl substituent is introduced into the nonselective /3-blockers alprenolol (11) and bunolol (12). The 4-hydroxyphenethyl group had no effect on cardioselectivity (the ratios of affinity being 1.3 and 1.5, respectively) but caused a 25-fold loss in affinity to the RVM receptor.…”

mentioning

confidence: 98%

Cardioselectivity of .beta.-adrenoceptor blocking agents. 1. 1-[(4-Hydroxyphenethyl)amino]-3-(aryloxy)propan-2-ols

Rzeszotarski¹,

Gibson²,

Eckelman³

et al. 1979

J. Med. Chem.

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A series of 1-[(4-hydroxyphenethyl)amino]-3-(aryloxy)propan-2-ols was synthesized together with several 1-[(3,4-dimethoxyphenethyl)amino]-3-(aryloxy)propan-2-ols. Their affinity to beta 1- and beta-2-adrenoceptors was determined and compared with the affinity of known beta-blockers. We were able to confirm the substantial cardioselectivity of 1-(3,4-dimethoxyphenethyl)-3-[(4-substituted aryl)oxy]propan-2-ols when compared to those with a 1-(4-hydroxyphenethyl) group. An increase in the size of the 4 substitutent of the 3-(aryloxy) moiety to caproamido leads to a substantially higher affinity for the beta 1--adrenoceptor of rat ventricular muscle in the presence of the 3,4-dimethoxyphenethyl than in the presence of the 4-hydroxyphenethyl or isopropyl group; this combination also gave the highest cardioselectivity.

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Alteration of relative affinities toward myocardial and vascular .beta. adrenoceptors induced by side-chain substitution of aryloxypropanolamines

Cited by 21 publications

References 12 publications

In vitro ACTIVITY OF RO363, A β₁‐ADRENOCEPTOR SELECTIVE AGONIST

In vitro ACTIVITY OF RO363, A β₁‐ADRENOCEPTOR SELECTIVE AGONIST

Synthesis and reactions of 1‐[1‐oxido‐2‐(3,4)‐pyridinyl]‐2‐methyloxiranes with nitrogen nucleophiles

Cardioselectivity of .beta.-adrenoceptor blocking agents. 1. 1-[(4-Hydroxyphenethyl)amino]-3-(aryloxy)propan-2-ols

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Alteration of relative affinities toward myocardial and vascular .beta. adrenoceptors induced by side-chain substitution of aryloxypropanolamines

Cited by 21 publications

References 12 publications

In vitro ACTIVITY OF RO363, A β1‐ADRENOCEPTOR SELECTIVE AGONIST

In vitro ACTIVITY OF RO363, A β1‐ADRENOCEPTOR SELECTIVE AGONIST

Synthesis and reactions of 1‐[1‐oxido‐2‐(3,4)‐pyridinyl]‐2‐methyloxiranes with nitrogen nucleophiles

Cardioselectivity of .beta.-adrenoceptor blocking agents. 1. 1-[(4-Hydroxyphenethyl)amino]-3-(aryloxy)propan-2-ols

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In vitro ACTIVITY OF RO363, A β₁‐ADRENOCEPTOR SELECTIVE AGONIST

In vitro ACTIVITY OF RO363, A β₁‐ADRENOCEPTOR SELECTIVE AGONIST