SYNTHESIS AND EVALUATION OF TRIMETOQUINOL DERIVATIVES - NOVEL THROMBOXANE A(2) PROSTAGLANDIN H-2 ANTAGONISTS WITH DIMINISHED BETA-ADRENERGIC AGONIST ACTIVITY

Trimetoquinol (TMQ, 1) is a unique catecholamine with a strong stereod ependence for agonism at beta-adrenergic (S much greater than R) and a ntagonism at thromboxane A(2)/prostaglandin H-2 (TP; R much greater th an S) receptors. Our laboratory has reported the effects of N-alkylati on and modification of the trisubstituted benzyl group in these recept or systems. For iodinated derivative 5, maintaining potency in TP rece ptor systems (112%) was coupled with maintaining limited potency in be ta-adrenergic receptor systems (34% for beta(1) and 47% for beta(2)) I n this study, several diverse TMQ derivatives were prepared to probe f or binding interactions specific to a particular receptor system. Plan ar amidine 2, which was designed to explore the importance of TMQ's ch iral 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 p otency (<3%) in both receptor systems. However, modification of the tr imethoxybenzyl group of TMQ to a 4-hydroxy-3-nitrobenzyl group (7) pro vided a unique lead for TMQ derivatives with significant potency in TP receptor systems (91%) and reduced potency in beta-adrenergic recepto r systems (4% for beta(1) and 19% for beta(2)).