Stereo-dependent inhibition of human platelet function by the optical isomers of trimetoquinol

Mayo, Joseph R.; Navran, Stephen S.; Huzoor-Akbar,; Miller, Duane D.; Feller, Dennis R.

doi:10.1016/0006-2952(81)90093-9

Cited by 30 publications

(12 citation statements)

References 8 publications

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“…The R(+)-isomer exhibits potent anti-aggregatory effects against 9,11-and 1 1,9-epoxymethano PGH2, arachidonic acid, and collagen but not against ADP (primary wave). The S(-)-isomer is much less active on aggregation but exhibits f-adrenoceptor agonist activity Mayo, Navran, Akbar, Miller & Feller, 1981). In our experiments R(+)-TMQ inhibited aggregation due to 11,9-epoxymethano PGH2 in the concentration range 0.1 to 1 gM.…”

Section: Discussionmentioning

confidence: 56%

Ligand binding to thromboxane receptors on human platelets: correlation with biological activity

Armstrong

Jones

Wilson

1983

British J Pharmacology

111

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Section: Discussionmentioning

confidence: 56%

Ligand binding to thromboxane receptors on human platelets: correlation with biological activity

Armstrong

Jones

Wilson

1983

British J Pharmacology

111

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“…The deposited solid was collected by vacuum filtration, rinsed with Et2O, and dried under vacuum at 56°C for 36 h to yield 106 mg (82%) of a rust-colored solid, dp 253-255°C (with bubbling). 1 H NMR (CD3OD): δ 8.05 (d, J ) 2.1 Hz, 1H, ArH ortho to NO2), 7.56 (dd, J ) 8.6 and 2.1 Hz, 1H, ArH para to NO2), 7.18 (d, J ) 8.6 Hz, 1H, ArH meta to NO2), 6.63 (s, 1H, ArH), 6.54 (s, 1H, ArH), 4.66 (t, J ) 7.2 Hz, 1H, ArCHRN), 3.51-3.41 (m, 2H, CH2), 3.31-3.23 (m, 1H, CH2), 3.14-3.05 (m, 1H, CH2), 3.01-2.92 (m, 2H, CH2). FAB MS: m/z 317.1 (MH + -HCl).…”

Section: 7-bis(benzyloxy)-1-(4-hydroxy-3-nitrobenzyl)-1234-tetramentioning

confidence: 99%

Synthesis and Evaluation of Trimetoquinol Derivatives: Novel Thromboxane A₂/Prostaglandin H₂ Antagonists with Diminished β-Adrenergic Agonist Activity

et al. 1997

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Trimetoquinol (TMQ, 1) is a unique catecholamine with a strong stereodependence for agonism at beta-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 beta-adrenergic receptor systems (34% for beta 1 and 47% for beta 2). 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 beta-adrenergic receptor systems (4% for beta 1 and 19% for beta 2).

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“…U46619, an epoxymethano-PGH2 ana logue is reported to be a TXA2-agonist [26] and has been used [8,16,27] to evaluate the TXA2 blocking activities to TMQ analogues and SQ 29,548. In our experiments, we found that there are no differences in reac tivity to TXA2 in vascular smooth muscle tissues of young and old animals.…”

Section: Discussionmentioning

confidence: 99%

“…The main hypoth esis under consideration is to establish whether there are age-dependent changes in the responses of the TXA2 receptor popula tion in vascular smooth muscle. In the present study we used rat thoracic aorta of young and old (senescent) ages to determine whether an age-dependent effect exists on vasocontractile responses to TXA2 and to antagonism by two TXA2 receptor antago nists, trimetoquinol (TMQ) [16] and SQ 29,548 [18]. …”

Section: Introductionmentioning

confidence: 99%

Effects of Thromboxane A<sub>2</sub> on Thoracic Aorta of Young and Old Rats: Use of Selective Thromboxane Receptor Antagonists

Shams

Wallace²,

Miller³

et al. 1990

Pharmacology

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Thromboxane A₂ (TXA₂) is a bioactive metabolite of arachidonic acid which produces vascular smooth muscle contraction and blood platelet aggregation. The goal of this study is to establish whether there are age-dependent differences of vascular contractility to TXA2. Thoracic aorta of F-344 rats of age 4–6 months (young) and 22–23 months (old) were used as a model to examine responses to U46619 [(¹⁵S)-hydroxy-11α, 9α-(epoxymetha-no)prosta-5Z,13E-dienoic acid; a TXA₂ agonist] alone or in the presence of prostanoid (SQ 29,548) or nonprostanoid (trimetoquinol, TMQ) endoperoxide/TXA₂ receptor antagonists. Maximal contractile responses (84 and 89% relative to KC1) and EC₅₀ values (23 and 55 nmol/l, respectively) to U46619 were the same in aortic strips of young and old animals. Experimentally determined pA₂ and pK_B values for SQ 29,548 and TMQ as antagonists of U46619-mediated contraction were unchanged in aorta of young (9.09 and 5.83, respectively) and old (9.41 and 6.10, respectively) rats. We conclude that the reactivity and population of TXA₂ receptors in rat vascular smooth muscle are unaffected by the aging process.

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Stereo-dependent inhibition of human platelet function by the optical isomers of trimetoquinol

Cited by 30 publications

References 8 publications

Ligand binding to thromboxane receptors on human platelets: correlation with biological activity

Ligand binding to thromboxane receptors on human platelets: correlation with biological activity

Synthesis and Evaluation of Trimetoquinol Derivatives: Novel Thromboxane A₂/Prostaglandin H₂ Antagonists with Diminished β-Adrenergic Agonist Activity

Effects of Thromboxane A<sub>2</sub> on Thoracic Aorta of Young and Old Rats: Use of Selective Thromboxane Receptor Antagonists

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Stereo-dependent inhibition of human platelet function by the optical isomers of trimetoquinol

Cited by 30 publications

References 8 publications

Ligand binding to thromboxane receptors on human platelets: correlation with biological activity

Ligand binding to thromboxane receptors on human platelets: correlation with biological activity

Synthesis and Evaluation of Trimetoquinol Derivatives: Novel Thromboxane A2/Prostaglandin H2 Antagonists with Diminished β-Adrenergic Agonist Activity

Effects of Thromboxane A<sub>2</sub> on Thoracic Aorta of Young and Old Rats: Use of Selective Thromboxane Receptor Antagonists

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Synthesis and Evaluation of Trimetoquinol Derivatives: Novel Thromboxane A₂/Prostaglandin H₂ Antagonists with Diminished β-Adrenergic Agonist Activity