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 D.
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).
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U2 - 10.1021/jm950896w
DO - 10.1021/jm950896w
M3 - Article
C2 - 9016331
AN - SCOPUS:0031023358
SN - 0022-2623
VL - 40
SP - 85
EP - 91
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 1
ER -