Synthesis and Evaluation of Trimetoquinol Derivatives:  Novel Thromboxane A₂/Prostaglandin H₂ Antagonists with Diminished β-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).

Iodinated Analogs of Trimetoquinol as Highly Potent and Selective β2-Adrenoceptor Ligands

“…In addition, demethylation of the 4‘-methoxy substituent of 2 to give 18 (p K i = 4.72) resulted in a similar 380-fold reduction in binding affinity. The very low binding affinity of 18 contrasts with a recent observation where 6,7-dihydroxy-1-(4‘-hydroxy-3‘-nitrobenzyl)-1,2,3,4-tetrahydroisoquinoline exhibited good binding affinity. By contrast, substitution of the same methoxy group with an amino moiety (i.e., 21c , p K i = 6.73) resulted in only a 3-fold decrease in affinity.…”

Synthesis and Neurotoxicity of Tetrahydroisoquinoline Derivatives for Studying Parkinson's Disease

“…34) Several publications have reported the preparation of 1-substituted TIQs via the Pictet-Spengler reaction or BischlerNapieralski reaction. [35][36][37] Venkov demonstrated the synthesis of 1-substituted N-acyl-TIQs from N-acyl-2-phenylethylamines and aldehyde catalyzed by acidic media. 38) Other reports of substituted TIQ synthesis include Kametani's phenolic cyclization of 3-hydroxyphenylethylamine with carbonyl compounds.…”

“…Reductive amination of (R)-1-phenylethylamine (35) with phenylsulfanylacetone gave two diastereomeric mixtures of sulfide (36) and (ent-37). The mixture of sulfoxide (37) and (ent-36) was synthesized from (S) 1-phenyletylamine (ent-35).…”