Design, synthesis, and in vitro evaluation of cyclic nitrones as free radical traps for the treatment of stroke.

Analogs of the cyclic nitrone free radical trap 1 (3,3-dimethyl-3,4-dihydroisoquinoline N-oxide, a cyclic analog of phenyl-tert-butylnitrone (PBN)) were prepared in which (1) the fused phenyl ring was replaced with a naphthalene ring, an electron rich heterocycle, or a dimethylphenol, (2) the nitrone-containing ring comprised five, six, or seven atoms, and (3) the gem-dimethyl group was replaced with spirocyclic groups. The most active antioxidant, which bears a dimethylphenol fused to a 7-membered ring nitrone (compound 6h), inhibited lipid peroxidation in vitro with an IC50 of 22 microM, a 75-fold improvement over that of 1. The previously observed correlation between lipophilicity and activity vs lipid peroxidation in vitro has been further substantiated and refined by this study. Moreover, certain classes of compounds (namely, dimethylphenols 6g,h and furan 6j) have now been found which are considerably more active in vitro than expected on the basis of their log k'(w) values.

Carbocyclic nucleosides as inhibitors of human tumor necrosis factor-alpha production: effects of the stereoisomers of (3-hydroxycyclopentyl)adenines.

A series of four structurally related carbocyclic nucleosides (6a, 6b, 10a, and 10b) were synthesized and evaluated for their ability to inhibit tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6) production from human primary macrophages. These compounds had little effect on the production of IL-1 beta and IL-6. It was determined that compound 10a was the most potent inhibitor of TNF-alpha production (IC50 = 10 microM), having 2-5-fold more activity compared to its enantiomer 10b or its diastereomers 6a and 6b. In addition, these compounds were also tested for their ability to protect mice against lethal challenges of lipopolysaccharide (LPS) and D-galactosamine (D-Gal). Compound 10a showed superior protective effects (100% protection) compared to its enantiomer 10b or its diastereomers 6a and 6b when it was administered to mice which were challenged with 3 times the LD100 dose of LPS.

MDL 201,307: a novel benzothiazepine modulator of multiple drug resistance.

A series of novel benzothiazepine derivatives were evaluated for their relative potential to reverse multiple drug resistance (MDR) phenotype in vitro as well as for their relative cardiovascular activity and neurotoxicity. Compounds were evaluated for antiMDR activity using Chinese hamster ovary cells with derived resistance to either vincristine or doxorubicin, or a human lymphoblastic leukemia line with resistance to vinblastine. Lead compounds with good antiMDR activity were further evaluated for their relative potential to exhibit cardiovascular and neurological pharmacodynamic activity. A single compound, MDL 201,307 with good antiMDR activity and low cardiovascular and neurologic activity was chosen for further study. In contrast to (R)-verapamil, MDL 201,307 showed only a weak potential to block calcium channels. Using a series of related murine fibrosarcoma cell lines (UV-2237M) with varying levels of resistance to doxorubicin, it was shown that MDL 201,307 augmented inhibition of growth due to doxorubicin. The antiMDR compound was also effective in enhancing the cytotoxicity of actinomycin-D and vinblastine although it was ineffective in increasing cytotoxicity of the nonMDR compound, 5FU. MDL 201,307 increased uptake and decreased efflux of doxorubicin suggesting that MDL 201,307 blocks the GP170-mediated efflux pump mechanism. MDL 201,307 represents a novel antiMDR agent with diminished potential for cardiovascular activity and neurologic interactions which presently limit many of the currently available first and second generations of antiMDR compounds.

Studies on the emetic and antiemetic properties of zacopride and its enantiomers.

In ferrets, the oral emetic activity of zacopride was compared with its R- and S-enantiomers. Increasing doses of 0.01, 0.1, 1.0, 10.0 and 31.6 mg/kg of zacopride or its 2 enantiomers were each administered at hourly intervals to separate groups of animals until emesis occurred. The emetic (100%) dose for zacopride and its S-enantiomer was 0.11 mg/kg p.o. (cumulative dose). The R-enantiomer at a cumulative dose of 42.71 mg/kg p.o. produced emesis in 25% of the animals. By the i.p. route zacopride and its S-enantiomer were more potent than the R-enantiomer in blocking the emetic activity of 0.1 mg/kg p.o. of zacopride. The involvement of 5-HT3 mechanisms is indicated by a correlation between zacopride and its enantiomers to cause and prevent emesis and their affinity at 5-HT3 binding sites. Further, the putative 5-HT3 agonists, 2-methyserotonin and phenylbiguanide, at 10 mg/kg p.o., produced emesis that was blocked by zacopride (0.1 mg/kg i.p.) or ICS 205-930 (1 mg/kg i.p.). The results suggest that in the ferret the S-enantiomer is predominantly responsible for both the emetic and antiemetic properties of zacopride and that 5-HT3 agonism and antagonism are involved in these actions.

The differential activities of R (+)- and S(-)-zacopride as 5-HT3 receptor antagonists.

R(+)- and S(-)-zacopride were assessed as potential 5-HT3 receptor antagonists in behavioural and biochemical tests. The S(-)isomer was more potent than the R(+)isomer to antagonise the hyperactivity induced by the injection of amphetamine or the infusion of dopamine into the nucleus accumbens in the rat. In contrast, the R(+)isomer was more potent to reduce the aversive behaviour of mice to a brightly illuminated environment and in a marmoset human threat test, to facilitate social interaction in rats, to increase performance in a mouse habituation test and prevent a scopolamine-induced impairment, and to antagonise the inhibitory effect of 2-methyl-5-hydroxytryptamine to reduce [3H]acetylcholine release in slices of the rat entorhinal cortex. In binding assays, [3H]S(-)-zacopride and [3H]R(+)-zacopride labelled homogenous populations of high-affinity binding sites in the rat entorhinal cortex, R(+)-zacopride compete for a further 10 to 20% of the binding of [3H]R(+)/S(-)-zacopride or [3H]R(+)-zacopride in excess of that competed for by (S)(-)-zacopride. It is concluded that both isomers of zacopride have potent but different pharmacological activities, with the possibility of different recognition sites to mediate their effects.

Emetic activity of zacopride in ferrets and its antagonism by pharmacological agents.

Zacopride administered orally was more emetic in fed than in fasted ferrets. The emetic activity of zacopride (0.1 mg/kg p.o.) was inhibited (100%) by 0.1 mg/kg i.p. of zacopride and 1 mg/kg i.p. of ICS 205-930. Haloperidol (3.16 mg/kg i.p.) and prochlorperazine (3.16 mg/kg i.p.) were weakly effective. N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide, a 5-HT1P antagonist, was inactive. Thus, the emetic activity of zacopride, like that of cisplatin, is blocked by 5-HT3 receptor antagonists.

Antagonism of [3H]zacopride binding to 5-HT3 recognition sites by its (R) and (S) enantiomers.

[3H]Zacopride exhibits high affinity (Kd less than or equal to 1 nM) for 5-HT3 binding sites (inhibited by ICS 205-930) in rabbit intestinal muscularis and vagus nerve, human jejunum, rat intestinal muscularis and rat brain cortex. Its binding was inhibited by several 5-HT3 antagonists that displayed similar rank orders of potency in the tissues examined. Zacopride's (S) enantiomer was significantly more potent than its (R) enantiomer (21- to 42-fold in rabbit and human; 8- to 12-fold in rat) as an inhibitor of [3H]zacopride binding. These studies indicate that the utility of [3H]zacopride as a high affinity 5-HT3 ligand resides with the (S) enantiomer.

Antimalarials. 10. Substituted 3-halo- and 3-methoxy-2-aryl-4-quinoline(di-n-butylaminomethyl)methanols.

Four 2-aryl-4-quinoline(di-n-butylaminomethyl)methanols with Br, Cl, F, or OMe in position 3 were synthesized by modifications of standard reactions. The antimalarial activity decreased with increased size of the 3-substituent. The 3-F-4',6,8-Cl3 compound was the most active (at 2.5 mg/kg) and was completely curative at 80 mg/kg against P. berghei in mice.