Iodinated analogs of trimetoquinol as highly potent and selective beta 2-adrenoceptor ligands.

A series of trimetoquinol (1, TMQ) analogs were designed and synthesized based on the lead compound 2, a diiodinated analog of trimetoquinol which exhibits improved selectivity for beta 2-versus beta 1-adrenoceptors (AR). To determine the influence of 1-benzyl substituents of trimetoquinol on beta 2-AR binding affinity and selectivity, we replaced and/or removed the 3'-, 4'-, and 5'-methoxy substituents of trimetoquinol. Replacement of the 4'-methoxy group of 2 with an amino (21c) or acetamido (15) moiety did not significantly alter beta 2-AR and thromboxane A2/prostaglandin H2 (TP) receptor affinity. Substitution with a 4'-hydroxy (18) or -iodo (21b) group did not significantly alter beta 2-AR affinity, but greatly reduced TP receptor affinity (380- and 1200-fold, respectively). Further, the beta 2-AR can accommodate larger substituents such as a benzamide at the 4'-position (26b). Other monoiodo derivatives (24, 26a) have similar or slightly lower affinity to both beta 2-AR and TP receptor compared to their diiodo analogs. Interestingly, removal of the 4'-substituent of 3',5'-diiodo analogs increased beta 2-AR affinity with little or no effect on beta 1-AR and TP binding. Thus, analog 21a displayed highly potent (pKi 9.52) and selective (beta 2/beta 1 = 600) binding affinity for beta 2-AR. On the other hand, trifluoromethyl substituents at the 3'- and 5'-positions (27) essentially abolished binding affinity at beta 2-AR and TP receptors. The differential binding effects of the aforementioned trimetoquinol modifications on the receptor systems may reflect differences in the binding pocket that interacts with the benzyl portion of trimetoquinol analogs. Thus, manipulation of the 1-benzyl moiety of trimetoquinol (1) has resulted in analogs that exhibit potent beta 2-AR binding affinity and significantly lower beta 1-AR and TP receptor affinities.

Halogen-substituted trimetoquinol analogs as thromboxane A2 receptor antagonists in platelets and aorta.

Trimetoquinol (TMQ) is a non-prostanoid compound that blocks prostaglandin H2/thromboxane A2 (TXA2) receptor-mediated responses initiated by a prostaglandin (PG) H2 analog, U46619, in human platelets and rat aorta. Ring fluorine-substituted TMQ analogs selectively antagonized PG-dependent human platelet activation induced by U46619, arachidonic acid, collagen, ADP or epinephrine; and were about 300-fold less potent as inhibitors of PG-independent responses mediated by thrombin or bacterial phospholipase C. For each inducer of the PG-dependent pathway, the rank order of inhibitory potency was identical (TMQ > 8-fluoro-TMQ > 5-fluoro- TMQ). Iodine substitution yielded a similar rank order of antagonism against U46619-induced platelet activation (TMQ > 8-iodo-TMQ > 5-iodo-TMQ), and all TMQ analogs inhibited platelet aggregation in whole blood as well as in platelet-rich plasma. Inhibition of specific [3H]SQ 29,548 binding by TMQ analogs was highly correlated with inhibition of functional responses to U46619. Radioligand binding experiments using TMQ analogs with rat platelets showed no interspecies difference in comparison with human platelets. The rank order of inhibitory potencies for the fluorinated (but not iodinated) TMQ analogs changed in rat thoracic aorta with 8-fluoro-TMQ > TMQ > or = 5-fluoro-TMQ as antagonists of U46619-induced vascular contraction. These findings demonstrate that the primary mechanism of antiplatelet action of TMQ analogs is related to a blockade of TXA2 receptor sites, and ring-halogenated TMQ analogs distinguish between TXA2-mediated functional responses in vascular smooth muscle and platelets.

Synthesis and platelet antiaggregatory activity of trimetoquinol analogs as endoperoxide/thromboxane A2 antagonists.

Trimetoquinol (TMQ) has activity as a beta-adrenergic agonist and as a platelet antiaggregatory agent. Recent reports from this and other laboratories have focused on the mechanism of inhibition of platelet function by TMQ and its analogs. Based on its competitive and stereoselective inhibition of thromboxane mimetic agents, TMQ was proposed as an endoperoxide/thromboxane A2 receptor antagonist; however, this mechanism has been questioned. A radiolabeled TMQ analog with high specific activity would aid in the elucidation of the actual mechanism of action. In the current research, modifications of the trimethoxy ring system of TMQ have been investigated. Replacement of one or two of the methoxy groups with iodine atoms leads to retention of platelet antiaggregatory activity and agonist blocking activity. Thus, these analogs have promise as potential radioligands since iodide exchange labeling can provide 125I-labeled compounds. Further, replacement of a methoxy group with either a nitro or amino functionality leads to decreased activity in platelet systems. These results suggest that the putative sites of interaction for the trimethoxy ring system of TMQ in platelet systems will tolerate large, lipid soluble groups but will not tolerate large changes in the electronic characteristics of the ring system.

5-fluoro- and 8-fluorotrimetoquinol: selective beta 2-adrenoceptor agonists.

The 5-fluoro and 8-fluoro analogues of trimetoquinol, TMQ, have been synthesized and evaluated for beta 2- and beta 1-adrenoceptor activity in guinea pig trachea and atria, respectively. The fluoro analogues of TMQ maintained potent beta 2-adrenoceptor agonist activity but had reduced beta 1-adrenoceptor agonist activity. The changes in beta 1-activity of these compounds were correlated to differences in phenolic pKa's. The beta 1- and beta 2-adrenoceptor actions of 2 and 3 were blocked in a competitive manner by propranolol. The enhanced beta 2/beta 1 selectivity for the analogues was found to be 8-fluoro analogue 3 greater than 5-fluoro analogue 2 greater than trimetoquinol (1).

6,7-Dichloro-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline . A structurally novel beta-adrenergic receptor blocking agent.

Replacement of the catecholic hydroxyl groups of the beta-adrenergic receptor agonist 6,7-dihydroxy-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline (trimetoquinol) with chloro substituents results in a compound with marked beta-adrenoceptor antagonist properties. This, therefore, parallels the similar transformation of the beta-adrenoreceptor agonist isoproterenol into the antagonist dichloroisoproterenol. In a test for inhibition of isoproterenol-induced enhancement of the rate of contraction of spontaneously beating guinea pig atrial pairs the resultant 6,7-dichloro-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline (6b) had a KB value of (6.7 +/- 2.3) X 10(-8) M. Although this is nearly 2 orders of magnitude less potent than propranolol (KB = 6.2 X 10(-10) M in this test), this compound represents the prototype of a new class of beta-adrenergic receptor blockers, and unlike dichloroisoproterenol it is not a partial agonist. It has physicochemical properties, e.g., pKa and distribution and partition coefficients, that differ from the prototypic beta-blockers. These altered properties might impart advantageous tissue distribution and altered pharmacological properties to the new molecule. This new beta-adrenoreceptor antagonist is suggested to merit further study.

Syntheses and beta-adrenergic agonist and antiaggregatory properties of N-substituted trimetoquinol analogues.

Trimetoquinol [1-(3,4,5-trimethoxybenzyl)-6,7- dihydroxy-1,2,3,4-tetrahydroisoquinoline, TMQ] is a potent beta-adrenergic receptor agonist and inhibitor of human platelet aggregation. Selective cleavage of O-benzyl groups in the presence of an N-benzyl group using HCl and formation of a cyclic sulfite ester from the reaction of a catechol with thionyl chloride were achieved. The N-substituents included methyl, benzyl, and beta-hydroxy- and beta-chloroethyl groups. Each N-substituted TMQ caused a concentration-dependent stimulation of beta 2 (trachea) and beta 1 (atria) adrenoceptor tissues and inhibition of 15(S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13(E)-dienoic acid (U46619, a thromboxane A2 mimetic) mediated human platelet activation. TMQ remained the most potent in the series. Structure-activity results indicated that the larger the N-substituent, the lower the beta-adrenergic activity but the higher the inhibition of platelet aggregatory activity. Thus, the structural requirements of these TMQ analogues for the two types of biological activity are different.

Synthesis, beta-adrenergic activity, and platelet antiaggregatory activity of a positional isomer of trimetoquinol: 1-(2',4',5'-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4,-tetrahydroisoquinoline.

A positional isomer of trimetoquinol (1), 1-(2',4',5'-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (3), was synthesized and found to possess less beta-adrenergic activity than 1 in isolated guinea pig atrial and tracheal preparations. The analogue 3 was an effective antiaggregatory agent in human and rabbit platelet-rich plasma preparations, while 1 was effective only as an inhibitor of arachidonic acid induced aggregation in human platelets. These findings indicate that both qualitative and quantitative differences in biological activity have occurred as a result of changing the position of the methoxy groups on the 1-benzyl substituent of 1.

Synthesis and beta-adrenoceptor activity of the erythro and threo isomers of substituted alpha-hydroxytrimetoquinol.

The synthesis and pharmacological activity of erythro and threo isomers of 1-(3',4',5'-trimethoxy-alpha-hydroxy-benzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, 2 and 3, are reported. The structural assignments of 2 and 3 are based upon NMR spectra of the 6,7-dibenzyl precursors, 6 and 10, and of the synthetic derivatives of 13alpha- and 13beta-hydroxy-2,3-(dibenzyloxy)-9,10,11-trimethoxytetrahydroprotoberberine, 8 and 12, respectively. The erythro isomer 2 was a more potent beta-adrenoceptor stimulant than the threo isomer 3 in guinea pig atrial, guinea pig tracheal, and rat adipocyte preparations. The differential activity of these compounds on lipolysis was favorably correlated to changes in the stimulation of adenylate cyclase activity and cAMP accumulation in rat adipocytes.

Synthesis of 1-substituted analogues of trimetoquinol possessing differential and selective beta-adrenergic properties.

The synthesis of the 1,1-disubstituted tetrahydroisoquinoline analogues, 1-methyl-1-(3,4,5-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2) and 1-benzyl-1-(3,4,5-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3), is described. The profile of beta-adrenergic activity for these analogues was determined and compared to that of trimetoquinol (1) in isolated guinea pig atrial, tracheal, and rat adipocyte preparations. Unexpected selective beta1-blocking activity in guinea pig trachea was noted with analogue 3. With the exception of 2 in guinea pig atria, 2 and 3 did not possess any beta-stimulant activity. Substitution at the 1 position of trimetoquinol (1) has revealed qualitative differences in beta-adrenergic activity.

Synthesis and biological evaluation of fragmented derivatives of tetrahydroisoquinolines. 2. Trimetoquinol studies.

The synthesis of N-(3',4',5'-trimethoxyphenylethyl)-3,4-dihydroxyphenylethylamine (2) and 1-(3,4,5-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (1) is presented. Comparative pharmacological effects of the optical isomers of 1 and compound 2 are reported in guinea pig atria, rat adipose tissue, guinea pig trachea, and guinea pig aortic strip preparations. In the beta-adrenoreceptor preparations, (-)-1 was shown to be more potent than (+)-1 or 2. Racemic 1 and 2 were shown to have equal alpha-antagonist properties in the inhibition of norepinephrine-induced contractions of guinea pig aorta.