Biomedical subjects
Publications and source records attributed to M L Go.
The synthesis of esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxy-estr-4-en-3-one) with acids containing a benzene ring is described, two methods of esterification being compared in terms of yield and convenience. The activities of these esters as long-acting contraceptive agents have been evaluated.
5-Methyl- and 5-ethyl-furylalkylcarboxylic esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) were prepared in high yield in the presence of thallous ethoxide. The activities of these compounds as long-acting contraceptive agents have been evaluated.
Esters of levonorgestrel (13 beta-ethyl-17 beta-ethynyl-17 beta-hydroxygon-4-en-3-one) with a variety of unsaturated carboxylic acids have been synthesized for evaluation as potential long-acting, injectable contraceptive agents.
The apparent partition coefficients (Papp.) of eight 4-aminoquinolines in 1-octanol/pH 7.4 buffered solutions have been determined and correlated with their reported antifilarial activities. Antifilarial activity appears to be present only in those 4-aminoquinolines which have log Papp. values falling within a narrow range of 2.8 to 3.2.
Ten amodiaquine analogues, which are hybridized molecules of amodiaquine and diethylcarbamazine, were designed and synthesized. Six analogues, all bearing a basic tertiary amino function at their side chain, were active against Plasmodium berghei in mice and inhibited the mobility of adult worms and microfilariae of Breinlia booliati in vitro. They were inactive against Litomosoides carinii in Mastomys natalensis. The most active antimalarial compound, 7-chloro-4-[alpha-[[N-(4-methyl-1-piperazinyl)carbonyl]amino]-4-hydroxy-m-toluidino]quinoline, had twice the activity of amodiaquine. O-Methylation and N-ethylation generally reduced antimalarial activity. Analogues which lack a basic tertiary amino function at their side chain were also lacking in both antimalarial and antifilarial activities.
The antimalarial agent, amodiaquine, is a potent inhibitor of AChE (Ki = 1.50 x 10(-9) M, pH 7.4, 25 degrees C). Both the protonated diethylamino and phenolic hydroxyl functions of amodiaquine are necessary for interaction with AChE. This suggests that the inhibition of AChE by amodiaquine may involve binding of the protonated diethylamino and phenolic hydroxyl functions to the anionic and esteric sites of the enzyme respectively. The anti-AChE property of amodiaquine may be related in some way to the gastrointestinal and central nervous system disturbances frequently encountered when large doses of amodiaquine are used for the treatment of malaria.
The characteristics of the inhibition of electric eel acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BChE) by the antimalarial agents mefloquine, chloroquine, amodiaquine and amopyroquine were determined. The antimalarials were found to be non-competitive inhibitors of both AChE and BChE. In both enzyme systems, inhibitory potencies were in the order amodiaquine greater than amopyroquine greater than chloroquine greater than mefloquine. The low inhibitory potency of mefloquine may account in part for the appearance of gastrointestinal and central nervous system disturbances only at high doses of the drug.
The effects of the antimalarial agent mefloquine on skeletal muscle and its neurotransmission were investigated on the isolated chick biventer cervicis and rat phrenic nerve hemidiaphragm. At concentrations of 64, 128 and 257 microM, mefloquine reduced twitch contraction responses to nerve stimulation, and inhibited carbachol- and KCl-induced contractures of avian muscle. Qualitatively similar responses were observed for chloroquine (257 microM) and quinine (512 microM) but the inhibitory effects of mefloquine were more pronounced and less readily reversible. On the rat phrenic nerve hemidiaphragm, mefloquine (50, 75 and 100 microM) inhibited twitch contractions stimulated indirectly via the nerve. When nerve transmission has been blocked with alpha-bungarotoxin, mefloquine inhibited twitch responses obtained by direct stimulation of the hemidiaphragm. The present findings indicate that its prime action seems to be on muscle contractility, possibly by inhibiting excitation-contraction coupling.
The effects of the antimalarial agent mefloquine on directly stimulated rat hemidiaphragm were investigated after nerve transmission had been blocked with alpha-bungarotoxin. Mefloquine (50 and 75 microM) caused contractures and diminished directly stimulated twitch responses. The mefloquine-induced contracture was significantly diminished in low Ca2+ Krebs-Henseleit solution and after pretreatment with phospholipase C. It was potentiated following an initial exposure to ryanodine. Mefloquine, as well as ryanodine, reduced the caffeine contractures obtained in low Ca2+ media. The results suggest that Ca(2+)-induced Ca2+ release, involving the action of mefloquine on some phospholipid component of the sarcolemma, appears to be important in the initiation of the contracture. The loss in caffeine response following pretreatment with mefloquine indicates that mefloquine also causes depletion of Ca2+ from sarcoplasmic reticulum stores.
The effects of the antimalarial agent, mefloquine, and its derivatives on Ca2+ uptake and release by crude microsomes from the rabbit skeletal muscle were investigated using a spectrophotometric method. These compounds diminished the rate of Ca2+ uptake and inhibited the Ca2+ pump ATPase activity of the microsomes. Except for quinine, they appear to have negligible effects on Ca2+ release channels. Of the compounds investigated, mefloquine had the most pronounced effect on Ca2+ uptake and was also the most potent (noncompetitive) inhibitor of Ca(2+)-ATPase (Ki: 53 microM). The ability of mefloquine to interfere with Ca2+ sequestration into the sarcoplasmic reticulum via inhibition of the Ca2+ pump ATPase, may explain some of its actions on the isolated skeletal muscle (relaxation, inhibition of twitch responses, diminution of caffeine contractures) observed in earlier studies. However, its contractile effects are less readily explained. The novel finding that mefloquine inhibits the Ca2+ pump ATPase of the skeletal muscle, suggests that it may have similar effects on the Ca(2+)-ATPases of other tissues.
The effects of the antimalarial drug, mefloquine, on the uptake and release of Ca2+ by crude microsomes from dog brain were investigated using a spectrophotometric method. Mefloquine inhibited the inositol-1,4,5-phosphate (IP3)-induced Ca2+ release with an IC50 of 42 microM, but was a weaker inhibitor of the uptake of Ca2+ into the vesicles (IC50: 272 microM). These effects of mefloquine are in contrast to its actions on Ca2+ uptake and release by skeletal muscle microsomes, where its predominant effect was seen to be the inhibition of Ca2+ uptake into the vesicles. Mefloquine was found to be more potent than quinine as a specific inhibitor of Ca2+ release from IP3-sensitive stores in dog brain microsomes. The possibility of the drug affecting cellular IP3-linked signal transduction processes should be considered.