Antagonism of prostaglandin-mediated responses in platelets and vascular smooth muscle by 13-azaprostanoic acid analogs. Evidence for selective blockade of thromboxane A2 responses

Huzoor-Akbar, Asoke Mukhopadhyay, Karen S. Anderson, Stephen S. Navran, Karl Romstedt, Duane Miller, Dennis R. Feller

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Studies were undertaken to examine the pharmacological properties and stereochemical requirements of a limited series of prostanoic acid analogs for inhibition of arachidonic acid (AA) and/ or endoperoxide (U46619)-mediated responses in human platelets and rat aorta. To assess the role of stereochemistry, a set of trans- and cis-isomers of 13-azaprostanoic acid (APA) and 11a-homo-13-azaprostanoic acid (HAPA) were prepared. Each prostanoic acid analog blocked AA- or U46619-induced aggregatory and secretory responses in platelets, and U46619-mediated contractions of rat aorta in a concentration-dependent manner (0.1 to 100 μM). The azaprostanoic acid analogs blocked responses to both inducers of platelet activation with ic50 values ranging from 3.4 to 27.5μM. Trans-APA was about 2- to 3-fold more active as an antagonist of serotonin release induced by AA or U46619 than the remaining analogs. The rank order of inhibitory potency (ic50; μM) for these analogs against U46619-induced serotonin release in human platelets was trans-APA (3.4) > cis-APA (8.9) = cis-HAPA (8.7) = trans-HAPA (9.1). Concentrations of the prostanoic acid analogs required to block these responses to AA and U46619 were similar, and the highest concentration used (100 μM) did not modify AA-induced malondialdehyde production in human platelet preparations. In contrast, the isomers of APA and HAPA were equally active as antagonists of U46619-indueed contractions of rat vascular tissue, possessing KB values varying from 7.1 to 13.2 μM. Each azaprostanoic acid analog shifted the concentration-response curve of U46619 in rat aorta to the right, indicating a competitive-type inhibition. In addition, the azoprostanoic acid analog (U51605) was a more potent competitive antagonist of U46619 in this preparation and possessed an average pKB value of 6.18. In summary, the results show that (1) expansion of the five-membered ring of APA to the six-membered ring analogs (HAPA) led to a retention of potent inhibitory activity against U46619 in human platelets and rat vascular smooth muscle, (2) the antiaggregatory and antisecretory actions of the azaprostanoic acid analogs were mediated by a blockade of the responses to AA and U46619, and not by an inhibition of AA metabolism, (3) the blocking activity for the APA isomers was stereoselective (trans > cis) whereas the isomers of HAPA were equally effective as inhibitors of platelet function; and (4) these azaprostanoic acid analogs act as selective endoperoxide (U46619)/thromboxane A2 antagonists in these two tissues.

Original languageEnglish (US)
Pages (from-to)641-647
Number of pages7
JournalBiochemical Pharmacology
Volume34
Issue number5
DOIs
StatePublished - Mar 1 1985
Externally publishedYes

Fingerprint

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Thromboxane A2
Platelets
Vascular Smooth Muscle
Prostaglandins
Muscle
Blood Platelets
Arachidonic Acid
Acids
Prostanoic Acids
Rats
Isomers
Aorta
NSC 153174
Inhibitory Concentration 50
13-azaprostanoic acid
Tissue
Enzyme inhibition
Serotonin Antagonists
Stereochemistry

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

Cite this

Antagonism of prostaglandin-mediated responses in platelets and vascular smooth muscle by 13-azaprostanoic acid analogs. Evidence for selective blockade of thromboxane A2 responses. / Huzoor-Akbar; Mukhopadhyay, Asoke; Anderson, Karen S.; Navran, Stephen S.; Romstedt, Karl; Miller, Duane; Feller, Dennis R.

In: Biochemical Pharmacology, Vol. 34, No. 5, 01.03.1985, p. 641-647.

Research output: Contribution to journalArticle

Huzoor-Akbar ; Mukhopadhyay, Asoke ; Anderson, Karen S. ; Navran, Stephen S. ; Romstedt, Karl ; Miller, Duane ; Feller, Dennis R. / Antagonism of prostaglandin-mediated responses in platelets and vascular smooth muscle by 13-azaprostanoic acid analogs. Evidence for selective blockade of thromboxane A2 responses. In: Biochemical Pharmacology. 1985 ; Vol. 34, No. 5. pp. 641-647.
@article{8c1ba6c4b48d4d23bdaebc979f27de5e,
title = "Antagonism of prostaglandin-mediated responses in platelets and vascular smooth muscle by 13-azaprostanoic acid analogs. Evidence for selective blockade of thromboxane A2 responses",
abstract = "Studies were undertaken to examine the pharmacological properties and stereochemical requirements of a limited series of prostanoic acid analogs for inhibition of arachidonic acid (AA) and/ or endoperoxide (U46619)-mediated responses in human platelets and rat aorta. To assess the role of stereochemistry, a set of trans- and cis-isomers of 13-azaprostanoic acid (APA) and 11a-homo-13-azaprostanoic acid (HAPA) were prepared. Each prostanoic acid analog blocked AA- or U46619-induced aggregatory and secretory responses in platelets, and U46619-mediated contractions of rat aorta in a concentration-dependent manner (0.1 to 100 μM). The azaprostanoic acid analogs blocked responses to both inducers of platelet activation with ic50 values ranging from 3.4 to 27.5μM. Trans-APA was about 2- to 3-fold more active as an antagonist of serotonin release induced by AA or U46619 than the remaining analogs. The rank order of inhibitory potency (ic50; μM) for these analogs against U46619-induced serotonin release in human platelets was trans-APA (3.4) > cis-APA (8.9) = cis-HAPA (8.7) = trans-HAPA (9.1). Concentrations of the prostanoic acid analogs required to block these responses to AA and U46619 were similar, and the highest concentration used (100 μM) did not modify AA-induced malondialdehyde production in human platelet preparations. In contrast, the isomers of APA and HAPA were equally active as antagonists of U46619-indueed contractions of rat vascular tissue, possessing KB values varying from 7.1 to 13.2 μM. Each azaprostanoic acid analog shifted the concentration-response curve of U46619 in rat aorta to the right, indicating a competitive-type inhibition. In addition, the azoprostanoic acid analog (U51605) was a more potent competitive antagonist of U46619 in this preparation and possessed an average pKB value of 6.18. In summary, the results show that (1) expansion of the five-membered ring of APA to the six-membered ring analogs (HAPA) led to a retention of potent inhibitory activity against U46619 in human platelets and rat vascular smooth muscle, (2) the antiaggregatory and antisecretory actions of the azaprostanoic acid analogs were mediated by a blockade of the responses to AA and U46619, and not by an inhibition of AA metabolism, (3) the blocking activity for the APA isomers was stereoselective (trans > cis) whereas the isomers of HAPA were equally effective as inhibitors of platelet function; and (4) these azaprostanoic acid analogs act as selective endoperoxide (U46619)/thromboxane A2 antagonists in these two tissues.",
author = "Huzoor-Akbar and Asoke Mukhopadhyay and Anderson, {Karen S.} and Navran, {Stephen S.} and Karl Romstedt and Duane Miller and Feller, {Dennis R.}",
year = "1985",
month = "3",
day = "1",
doi = "10.1016/0006-2952(85)90258-8",
language = "English (US)",
volume = "34",
pages = "641--647",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "5",

}

TY - JOUR

T1 - Antagonism of prostaglandin-mediated responses in platelets and vascular smooth muscle by 13-azaprostanoic acid analogs. Evidence for selective blockade of thromboxane A2 responses

AU - Huzoor-Akbar,

AU - Mukhopadhyay, Asoke

AU - Anderson, Karen S.

AU - Navran, Stephen S.

AU - Romstedt, Karl

AU - Miller, Duane

AU - Feller, Dennis R.

PY - 1985/3/1

Y1 - 1985/3/1

N2 - Studies were undertaken to examine the pharmacological properties and stereochemical requirements of a limited series of prostanoic acid analogs for inhibition of arachidonic acid (AA) and/ or endoperoxide (U46619)-mediated responses in human platelets and rat aorta. To assess the role of stereochemistry, a set of trans- and cis-isomers of 13-azaprostanoic acid (APA) and 11a-homo-13-azaprostanoic acid (HAPA) were prepared. Each prostanoic acid analog blocked AA- or U46619-induced aggregatory and secretory responses in platelets, and U46619-mediated contractions of rat aorta in a concentration-dependent manner (0.1 to 100 μM). The azaprostanoic acid analogs blocked responses to both inducers of platelet activation with ic50 values ranging from 3.4 to 27.5μM. Trans-APA was about 2- to 3-fold more active as an antagonist of serotonin release induced by AA or U46619 than the remaining analogs. The rank order of inhibitory potency (ic50; μM) for these analogs against U46619-induced serotonin release in human platelets was trans-APA (3.4) > cis-APA (8.9) = cis-HAPA (8.7) = trans-HAPA (9.1). Concentrations of the prostanoic acid analogs required to block these responses to AA and U46619 were similar, and the highest concentration used (100 μM) did not modify AA-induced malondialdehyde production in human platelet preparations. In contrast, the isomers of APA and HAPA were equally active as antagonists of U46619-indueed contractions of rat vascular tissue, possessing KB values varying from 7.1 to 13.2 μM. Each azaprostanoic acid analog shifted the concentration-response curve of U46619 in rat aorta to the right, indicating a competitive-type inhibition. In addition, the azoprostanoic acid analog (U51605) was a more potent competitive antagonist of U46619 in this preparation and possessed an average pKB value of 6.18. In summary, the results show that (1) expansion of the five-membered ring of APA to the six-membered ring analogs (HAPA) led to a retention of potent inhibitory activity against U46619 in human platelets and rat vascular smooth muscle, (2) the antiaggregatory and antisecretory actions of the azaprostanoic acid analogs were mediated by a blockade of the responses to AA and U46619, and not by an inhibition of AA metabolism, (3) the blocking activity for the APA isomers was stereoselective (trans > cis) whereas the isomers of HAPA were equally effective as inhibitors of platelet function; and (4) these azaprostanoic acid analogs act as selective endoperoxide (U46619)/thromboxane A2 antagonists in these two tissues.

AB - Studies were undertaken to examine the pharmacological properties and stereochemical requirements of a limited series of prostanoic acid analogs for inhibition of arachidonic acid (AA) and/ or endoperoxide (U46619)-mediated responses in human platelets and rat aorta. To assess the role of stereochemistry, a set of trans- and cis-isomers of 13-azaprostanoic acid (APA) and 11a-homo-13-azaprostanoic acid (HAPA) were prepared. Each prostanoic acid analog blocked AA- or U46619-induced aggregatory and secretory responses in platelets, and U46619-mediated contractions of rat aorta in a concentration-dependent manner (0.1 to 100 μM). The azaprostanoic acid analogs blocked responses to both inducers of platelet activation with ic50 values ranging from 3.4 to 27.5μM. Trans-APA was about 2- to 3-fold more active as an antagonist of serotonin release induced by AA or U46619 than the remaining analogs. The rank order of inhibitory potency (ic50; μM) for these analogs against U46619-induced serotonin release in human platelets was trans-APA (3.4) > cis-APA (8.9) = cis-HAPA (8.7) = trans-HAPA (9.1). Concentrations of the prostanoic acid analogs required to block these responses to AA and U46619 were similar, and the highest concentration used (100 μM) did not modify AA-induced malondialdehyde production in human platelet preparations. In contrast, the isomers of APA and HAPA were equally active as antagonists of U46619-indueed contractions of rat vascular tissue, possessing KB values varying from 7.1 to 13.2 μM. Each azaprostanoic acid analog shifted the concentration-response curve of U46619 in rat aorta to the right, indicating a competitive-type inhibition. In addition, the azoprostanoic acid analog (U51605) was a more potent competitive antagonist of U46619 in this preparation and possessed an average pKB value of 6.18. In summary, the results show that (1) expansion of the five-membered ring of APA to the six-membered ring analogs (HAPA) led to a retention of potent inhibitory activity against U46619 in human platelets and rat vascular smooth muscle, (2) the antiaggregatory and antisecretory actions of the azaprostanoic acid analogs were mediated by a blockade of the responses to AA and U46619, and not by an inhibition of AA metabolism, (3) the blocking activity for the APA isomers was stereoselective (trans > cis) whereas the isomers of HAPA were equally effective as inhibitors of platelet function; and (4) these azaprostanoic acid analogs act as selective endoperoxide (U46619)/thromboxane A2 antagonists in these two tissues.

UR - http://www.scopus.com/inward/record.url?scp=0021998099&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0021998099&partnerID=8YFLogxK

U2 - 10.1016/0006-2952(85)90258-8

DO - 10.1016/0006-2952(85)90258-8

M3 - Article

VL - 34

SP - 641

EP - 647

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 5

ER -