Synthesis and evaluation of trimetoquinol derivatives: novel thromboxane A2/prostaglandin H2 antagonists with diminished beta-adrenergic agonist activity.
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).
Christoff
J J
JJ
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus 43210, USA.
Bradley
L
L
Miller
D D
DD
Lei
L
L
Rodriguez
F
F
Fraundorfer
P
P
Romstedt
K
K
Shams
G
G
Feller
D R
DR
D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D006168:Guinea Pigs; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects; D044262:Prostaglandin H2; D011463:Prostaglandins H / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013237:Stereoisomerism; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D014213:Tretoquinol / Q000031:analogs & derivatives*
D000318:Adrenergic beta-Agonists; D011463:Prostaglandins H; D011982:Receptors, Prostaglandin; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D044262:Prostaglandin H2; D013928:Thromboxane A2; D014213:Tretoquinol