Synthesis and evaluation of trimetoquinol derivatives

Novel thromboxane A2/prostaglandin H2 antagonists with diminished β-adrenergic agonist activity

Jeffrey J. Christoff, Luke Bradley, Duane Miller, Longping Lei, Fernando Rodriguez, Paul Fraundorfer, Karl Romstedt, Gamal Shams, Dennis R. Feller

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Trimetoquinol (TMQ, 1) is a unique catecholamine with a strong stereodependence for agonism at β-adrenergic (S >> R) and antagonism at thromboxane A2/prostaglandin H2 (TP; R >> S) receptors. Our laboratory has reported the effects of N-alkylation and modification of the trisubstituted benzyl group in these receptor systems. For iodinated derivative 5, maintaining potency in TP receptor systems (112%) was coupled with maintaining limited potency in β-adrenergic receptor systems (34% for β1 and 47% for β2). In this study, several diverse TMQ derivatives were prepared to probe for binding interactions specific to a particular receptor system. Planar amidine 2, which was designed to explore the importance of TMQ's chiral center, showed a dramatic loss of potency (<1%) in each receptor system. Likewise, the homologation of a previously described N-benzyl derivative (3) to the N-phenylethyl derivative 4 also showed reduced potency (<3%) in both receptor systems. However, modification of the trimethoxybenzyl group of TMQ to a 4-hydroxy-3-nitrobenzyl group (7) provided a unique lead for TMQ derivatives with significant potency in TP receptor systems (91%) and reduced potency in β-adrenergic receptor systems (4% for β1 and 19% for β2).

Original languageEnglish (US)
Pages (from-to)85-91
Number of pages7
JournalJournal of Medicinal Chemistry
Volume40
Issue number1
DOIs
StatePublished - Jan 3 1997

Fingerprint

Tretoquinol
Thromboxane Receptors
Prostaglandin H2
Prostaglandin Antagonists
Adrenergic Agonists
Thromboxane A2
Adrenergic Receptors
Amidines
Alkylation
Adrenergic Agents
Catecholamines

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and evaluation of trimetoquinol derivatives : Novel thromboxane A2/prostaglandin H2 antagonists with diminished β-adrenergic agonist activity. / Christoff, Jeffrey J.; Bradley, Luke; Miller, Duane; Lei, Longping; Rodriguez, Fernando; Fraundorfer, Paul; Romstedt, Karl; Shams, Gamal; Feller, Dennis R.

In: Journal of Medicinal Chemistry, Vol. 40, No. 1, 03.01.1997, p. 85-91.

Research output: Contribution to journalArticle

Christoff, Jeffrey J. ; Bradley, Luke ; Miller, Duane ; Lei, Longping ; Rodriguez, Fernando ; Fraundorfer, Paul ; Romstedt, Karl ; Shams, Gamal ; Feller, Dennis R. / Synthesis and evaluation of trimetoquinol derivatives : Novel thromboxane A2/prostaglandin H2 antagonists with diminished β-adrenergic agonist activity. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 1. pp. 85-91.
@article{48683b3f349249629d6f8658f8740af7,
title = "Synthesis and evaluation of trimetoquinol derivatives: Novel thromboxane A2/prostaglandin H2 antagonists with diminished β-adrenergic agonist activity",
abstract = "Trimetoquinol (TMQ, 1) is a unique catecholamine with a strong stereodependence for agonism at β-adrenergic (S >> R) and antagonism at thromboxane A2/prostaglandin H2 (TP; R >> S) receptors. Our laboratory has reported the effects of N-alkylation and modification of the trisubstituted benzyl group in these receptor systems. For iodinated derivative 5, maintaining potency in TP receptor systems (112{\%}) was coupled with maintaining limited potency in β-adrenergic receptor systems (34{\%} for β1 and 47{\%} for β2). In this study, several diverse TMQ derivatives were prepared to probe for binding interactions specific to a particular receptor system. Planar amidine 2, which was designed to explore the importance of TMQ's chiral center, showed a dramatic loss of potency (<1{\%}) in each receptor system. Likewise, the homologation of a previously described N-benzyl derivative (3) to the N-phenylethyl derivative 4 also showed reduced potency (<3{\%}) in both receptor systems. However, modification of the trimethoxybenzyl group of TMQ to a 4-hydroxy-3-nitrobenzyl group (7) provided a unique lead for TMQ derivatives with significant potency in TP receptor systems (91{\%}) and reduced potency in β-adrenergic receptor systems (4{\%} for β1 and 19{\%} for β2).",
author = "Christoff, {Jeffrey J.} and Luke Bradley and Duane Miller and Longping Lei and Fernando Rodriguez and Paul Fraundorfer and Karl Romstedt and Gamal Shams and Feller, {Dennis R.}",
year = "1997",
month = "1",
day = "3",
doi = "10.1021/jm950896w",
language = "English (US)",
volume = "40",
pages = "85--91",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "1",

}

TY - JOUR

T1 - Synthesis and evaluation of trimetoquinol derivatives

T2 - Novel thromboxane A2/prostaglandin H2 antagonists with diminished β-adrenergic agonist activity

AU - Christoff, Jeffrey J.

AU - Bradley, Luke

AU - Miller, Duane

AU - Lei, Longping

AU - Rodriguez, Fernando

AU - Fraundorfer, Paul

AU - Romstedt, Karl

AU - Shams, Gamal

AU - Feller, Dennis R.

PY - 1997/1/3

Y1 - 1997/1/3

N2 - Trimetoquinol (TMQ, 1) is a unique catecholamine with a strong stereodependence for agonism at β-adrenergic (S >> R) and antagonism at thromboxane A2/prostaglandin H2 (TP; R >> S) receptors. Our laboratory has reported the effects of N-alkylation and modification of the trisubstituted benzyl group in these receptor systems. For iodinated derivative 5, maintaining potency in TP receptor systems (112%) was coupled with maintaining limited potency in β-adrenergic receptor systems (34% for β1 and 47% for β2). In this study, several diverse TMQ derivatives were prepared to probe for binding interactions specific to a particular receptor system. Planar amidine 2, which was designed to explore the importance of TMQ's chiral center, showed a dramatic loss of potency (<1%) in each receptor system. Likewise, the homologation of a previously described N-benzyl derivative (3) to the N-phenylethyl derivative 4 also showed reduced potency (<3%) in both receptor systems. However, modification of the trimethoxybenzyl group of TMQ to a 4-hydroxy-3-nitrobenzyl group (7) provided a unique lead for TMQ derivatives with significant potency in TP receptor systems (91%) and reduced potency in β-adrenergic receptor systems (4% for β1 and 19% for β2).

AB - Trimetoquinol (TMQ, 1) is a unique catecholamine with a strong stereodependence for agonism at β-adrenergic (S >> R) and antagonism at thromboxane A2/prostaglandin H2 (TP; R >> S) receptors. Our laboratory has reported the effects of N-alkylation and modification of the trisubstituted benzyl group in these receptor systems. For iodinated derivative 5, maintaining potency in TP receptor systems (112%) was coupled with maintaining limited potency in β-adrenergic receptor systems (34% for β1 and 47% for β2). In this study, several diverse TMQ derivatives were prepared to probe for binding interactions specific to a particular receptor system. Planar amidine 2, which was designed to explore the importance of TMQ's chiral center, showed a dramatic loss of potency (<1%) in each receptor system. Likewise, the homologation of a previously described N-benzyl derivative (3) to the N-phenylethyl derivative 4 also showed reduced potency (<3%) in both receptor systems. However, modification of the trimethoxybenzyl group of TMQ to a 4-hydroxy-3-nitrobenzyl group (7) provided a unique lead for TMQ derivatives with significant potency in TP receptor systems (91%) and reduced potency in β-adrenergic receptor systems (4% for β1 and 19% for β2).

UR - http://www.scopus.com/inward/record.url?scp=0031023358&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031023358&partnerID=8YFLogxK

U2 - 10.1021/jm950896w

DO - 10.1021/jm950896w

M3 - Article

VL - 40

SP - 85

EP - 91

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 1

ER -