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

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).