title: Synthesis and evaluation of trimetoquinol derivatives: novel thromboxane A2/prostaglandin H2 antagonists with diminished beta-adrenergic agonist activity.
abstract: 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).
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus 43210, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Christoff
authors.forename: L
authors.initials: L
authors.lastname: Bradley
authors.forename: D D
authors.initials: DD
authors.lastname: Miller
authors.forename: L
authors.initials: L
authors.lastname: Lei
authors.forename: F
authors.initials: F
authors.lastname: Rodriguez
authors.forename: P
authors.initials: P
authors.lastname: Fraundorfer
authors.forename: K
authors.initials: K
authors.lastname: Romstedt
authors.forename: G
authors.initials: G
authors.lastname: Shams
authors.forename: D R
authors.initials: DR
authors.lastname: Feller
mesh_terms: 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*
chemical_list: D000318:Adrenergic beta-Agonists; D011463:Prostaglandins H; D011982:Receptors, Prostaglandin; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D044262:Prostaglandin H2; D013928:Thromboxane A2; D014213:Tretoquinol