A rationale is presented for investigating aci-reductone 2-hydroxytetronic acids as antilipidemic drugs. These compounds are lipophilic Brönsted acids capable of forming water-soluble anions having biologically relevant redox potentials. The inhibitory effects of 4-(4-chlorophenyl)-2-hydroxytetronic acid (2a) on human platelet aggregation and [14C]serotonin secretion were compared with clofibric acid (1b), the hydrolysis product of clofibrate (1a). In cholesterol-fed rats, this analogue was superior to clofibrate as a hypocholesterolemic drug and modifier of heparin-MnCl2 precipitated lipoprotein cholesterol to alpha-lipoprotein cholesterol ratios. Whereas clofibrate (1a) produced hepatomegaly, this effect was not observed for the tetronic acid 2a.

The synthesis and biological evaluation of 7,8-dihydroxy (2) and 7,8-methylenedioxy (3) analogues of 1-[(3,4,5-trimethyoxyphenyl)methyl]-2,3,4,5-tetradhyo-1H-2-b enzazepine on beta-adrenoceptor systems and human platelets were undertaken and compared with trimetoquinol (TMQ, 1). Whereas 1 is a potent beta-adrenoceptor agonist in guinea pig atria and trachea (pD2 = 8.2), analogue 2 was marginally effective at relaxing guinea pig tracheal smooth muscle (pD2 = 4.4) and inactive as an agonist on guinea pig atria. Analogues 2 and 3 were inhibitors of phospholipase C (PLC; from Clostridium perfringens) induced and secondary wave of ADP-induced aggregation responses and inactive against low-dose thrombin-induced or stable endoperoxide (U46619) induced human platelet aggregation. Against ADP-induced serotonin secretion, 3 was 9-fold more active than analogue 2. Further, the rank order of TMQ isomers and 3 as inhibitors of PLC-induced platelet aggregation, serotonin secretion, and phosphatidylinositol degradation was identical (3 greater than (S)-(-)-1 greater than (R)-(+)-1). The results suggest that these compounds are blocking the action of PLC by interfering with phosphatidylinositol turnover in platelet membranes. The inhibition of ADP-induced responses in human platelets by analogues 2 and 3 also suggests a site of inhibition at a level of arachidonic acid release. Thus, ring expansion of 1 as in the benzazepine analogues 2 and 3 has allowed us to develop selective inhibitors of platelet function that lack significant beta-adrenoceptor activity.

There is a stereoselective difference in the interaction of the hexobarbital enantiomers with rat liver microsomes. The metabolism of the hexobarbital isomers was elevated in microsomes isolated from rats pretreated with phenobarbital and the (+)-isomer metabolized to a greater degree in control and phenobarbital-induced preparations. (+)-Hexobarbital was observed to be more effective than the (–)-isomer in the stimulation of endogenous NADPH oxidation and inhibition of ethylmorphine N-demethylation. In binding spectral experiments, the (+)-isomer exhibited larger A_max (maximum absorbance) values and slightly lower apparent Ks (spectral dissociation) constants than the (–)-form in control and phenobarbital-induced microsomal preparations.

A systematic series of methyl (2 and 3) and dimethyl (4) analogues of trimetoquinol (1) were synthesized and evaluated for their beta 1 (atria) and beta 2 (trachea) and adrenoceptor activities. Structural assignments for the erythro (2) and the threo (3) diastereoisomers of 1-(3,4,5-trimethoxy-alpha-methylbenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline were based on NMR spectra of the 6,7-dibenzyl precursors 15 and 16, respectively, and on the synthetic derivatives of cis- and trans-13-methyl-2,3-bis(benzyloxy)-9,10,11-trimethoxytetrahydroprotoberberine (18 and 17). The rank order of beta 2-agonist activity for these compounds was 3 greater than 1 greater than 2 greater than 4. The rank order of activity as beta 1 agonists on the guinea pig atria is 1 greater than 3 greater than 2, and 4 was inactive. The methylated analogues show selectivity for beta 2 receptors in our preliminary pharmacological studies. The threo isomer 3 is the most potent and selective beta 2 stimulant reported to date in the tetrahydroisoquinoline class.