Synthesis and evaluation of trimetoquinol derivatives: Novel thromboxane A2/prostaglandin H2 antagonists with diminished β-adrenergic agonist activity

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

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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