Pharmacological evaluation of the β-adrenoceptor agonist and thromboxane antagonist properties of N-substituted trimetoquinol analogues

Joanne S. Fedyna, Adeboye Adejare, Duane Miller, Dennis R. Feller

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The β1- and β2-adrenoceptor agonist and U46619 (a thromboxane A2 agonist) antagonist properties of trimetoquinol (TMQ, I) and its optical isomers, and N-substituted TMQ analogues (methyl, II; 2-hydroxyethyl, III; cyclic sulfite N-2-chloroethyl, IV; 2-chloroethyl, V; benzyl, VI) were studied in guinea pig atria and trachea and rat aorta respectively. All compounds gave concentration-dependent responses inatria and trachea, and the rank order of β-adrenoceptor agonist potency was I>II>III>IV>V>VI. Whereas N-substitution reduced potency for β-agonism, the β21-selectivity ratio was enhanced by increasing the size of the N-substituent. All analogues possessed equal or greater (up to 41-fold more) β2-selectivity than I. Propanolol was a competitive antagonist of selected TMQ analogues in guinea pig trachea and atria, thus confirming the β-adrenoceptor actions of these drugs. The optical isomers of TMQ gave a rank order of agonist potency of S(-)-TMQ>R(+)-TMQ, and a β21-selectivity equal to or greater than racemic-TMQ. Each TMQ analogue also blocked the contractile responses of U46619 in rat aorta in a competitive manner, and the rank order of inhibition of U46619-induced contraction in rat aorta was I>VI>II=III>IV>V. N-Benzyl TMQ (VI) possessed the greatest potency for U46619 blockade and β21-selectivity ratio of the N-substituted analogues. The results show that varying the N-substituents on TMQ produces compounds which retain β2-selectivity and give a different activity profile for β-adrenoceptor activation vs. endoperoxide/thromboxane A2 antagonism.

Original languageEnglish (US)
Pages (from-to)161-171
Number of pages11
JournalEuropean Journal of Pharmacology
Volume135
Issue number2
DOIs
StatePublished - Mar 17 1987
Externally publishedYes

Fingerprint

Tretoquinol
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Thromboxanes
Adrenergic Receptors
Trachea
Pharmacology
Aorta
Thromboxane A2
Guinea Pigs
Sulfites
Propranolol
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Pharmacological evaluation of the β-adrenoceptor agonist and thromboxane antagonist properties of N-substituted trimetoquinol analogues. / Fedyna, Joanne S.; Adejare, Adeboye; Miller, Duane; Feller, Dennis R.

In: European Journal of Pharmacology, Vol. 135, No. 2, 17.03.1987, p. 161-171.

Research output: Contribution to journalArticle

@article{b03d84836ee54963ad975f0dab937a21,
title = "Pharmacological evaluation of the β-adrenoceptor agonist and thromboxane antagonist properties of N-substituted trimetoquinol analogues",
abstract = "The β1- and β2-adrenoceptor agonist and U46619 (a thromboxane A2 agonist) antagonist properties of trimetoquinol (TMQ, I) and its optical isomers, and N-substituted TMQ analogues (methyl, II; 2-hydroxyethyl, III; cyclic sulfite N-2-chloroethyl, IV; 2-chloroethyl, V; benzyl, VI) were studied in guinea pig atria and trachea and rat aorta respectively. All compounds gave concentration-dependent responses inatria and trachea, and the rank order of β-adrenoceptor agonist potency was I>II>III>IV>V>VI. Whereas N-substitution reduced potency for β-agonism, the β2/β1-selectivity ratio was enhanced by increasing the size of the N-substituent. All analogues possessed equal or greater (up to 41-fold more) β2-selectivity than I. Propanolol was a competitive antagonist of selected TMQ analogues in guinea pig trachea and atria, thus confirming the β-adrenoceptor actions of these drugs. The optical isomers of TMQ gave a rank order of agonist potency of S(-)-TMQ>R(+)-TMQ, and a β2/β1-selectivity equal to or greater than racemic-TMQ. Each TMQ analogue also blocked the contractile responses of U46619 in rat aorta in a competitive manner, and the rank order of inhibition of U46619-induced contraction in rat aorta was I>VI>II=III>IV>V. N-Benzyl TMQ (VI) possessed the greatest potency for U46619 blockade and β2/β1-selectivity ratio of the N-substituted analogues. The results show that varying the N-substituents on TMQ produces compounds which retain β2-selectivity and give a different activity profile for β-adrenoceptor activation vs. endoperoxide/thromboxane A2 antagonism.",
author = "Fedyna, {Joanne S.} and Adeboye Adejare and Duane Miller and Feller, {Dennis R.}",
year = "1987",
month = "3",
day = "17",
doi = "10.1016/0014-2999(87)90608-X",
language = "English (US)",
volume = "135",
pages = "161--171",
journal = "European Journal of Pharmacology",
issn = "0014-2999",
publisher = "Elsevier",
number = "2",

}

TY - JOUR

T1 - Pharmacological evaluation of the β-adrenoceptor agonist and thromboxane antagonist properties of N-substituted trimetoquinol analogues

AU - Fedyna, Joanne S.

AU - Adejare, Adeboye

AU - Miller, Duane

AU - Feller, Dennis R.

PY - 1987/3/17

Y1 - 1987/3/17

N2 - The β1- and β2-adrenoceptor agonist and U46619 (a thromboxane A2 agonist) antagonist properties of trimetoquinol (TMQ, I) and its optical isomers, and N-substituted TMQ analogues (methyl, II; 2-hydroxyethyl, III; cyclic sulfite N-2-chloroethyl, IV; 2-chloroethyl, V; benzyl, VI) were studied in guinea pig atria and trachea and rat aorta respectively. All compounds gave concentration-dependent responses inatria and trachea, and the rank order of β-adrenoceptor agonist potency was I>II>III>IV>V>VI. Whereas N-substitution reduced potency for β-agonism, the β2/β1-selectivity ratio was enhanced by increasing the size of the N-substituent. All analogues possessed equal or greater (up to 41-fold more) β2-selectivity than I. Propanolol was a competitive antagonist of selected TMQ analogues in guinea pig trachea and atria, thus confirming the β-adrenoceptor actions of these drugs. The optical isomers of TMQ gave a rank order of agonist potency of S(-)-TMQ>R(+)-TMQ, and a β2/β1-selectivity equal to or greater than racemic-TMQ. Each TMQ analogue also blocked the contractile responses of U46619 in rat aorta in a competitive manner, and the rank order of inhibition of U46619-induced contraction in rat aorta was I>VI>II=III>IV>V. N-Benzyl TMQ (VI) possessed the greatest potency for U46619 blockade and β2/β1-selectivity ratio of the N-substituted analogues. The results show that varying the N-substituents on TMQ produces compounds which retain β2-selectivity and give a different activity profile for β-adrenoceptor activation vs. endoperoxide/thromboxane A2 antagonism.

AB - The β1- and β2-adrenoceptor agonist and U46619 (a thromboxane A2 agonist) antagonist properties of trimetoquinol (TMQ, I) and its optical isomers, and N-substituted TMQ analogues (methyl, II; 2-hydroxyethyl, III; cyclic sulfite N-2-chloroethyl, IV; 2-chloroethyl, V; benzyl, VI) were studied in guinea pig atria and trachea and rat aorta respectively. All compounds gave concentration-dependent responses inatria and trachea, and the rank order of β-adrenoceptor agonist potency was I>II>III>IV>V>VI. Whereas N-substitution reduced potency for β-agonism, the β2/β1-selectivity ratio was enhanced by increasing the size of the N-substituent. All analogues possessed equal or greater (up to 41-fold more) β2-selectivity than I. Propanolol was a competitive antagonist of selected TMQ analogues in guinea pig trachea and atria, thus confirming the β-adrenoceptor actions of these drugs. The optical isomers of TMQ gave a rank order of agonist potency of S(-)-TMQ>R(+)-TMQ, and a β2/β1-selectivity equal to or greater than racemic-TMQ. Each TMQ analogue also blocked the contractile responses of U46619 in rat aorta in a competitive manner, and the rank order of inhibition of U46619-induced contraction in rat aorta was I>VI>II=III>IV>V. N-Benzyl TMQ (VI) possessed the greatest potency for U46619 blockade and β2/β1-selectivity ratio of the N-substituted analogues. The results show that varying the N-substituents on TMQ produces compounds which retain β2-selectivity and give a different activity profile for β-adrenoceptor activation vs. endoperoxide/thromboxane A2 antagonism.

UR - http://www.scopus.com/inward/record.url?scp=0023107737&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0023107737&partnerID=8YFLogxK

U2 - 10.1016/0014-2999(87)90608-X

DO - 10.1016/0014-2999(87)90608-X

M3 - Article

VL - 135

SP - 161

EP - 171

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

IS - 2

ER -