Dimethyl Analogues Research Articles

Potency and selectivity of methyl analogues of prostaglandin E2 on rat gastrointestinal function.

1 The potency and selectivity of action of prostaglandin E2 and its (15S)- or (15R)-15 methyl and 16, 16 dimethyl analogues on gastrointestinal function have been studied in the rat. 2 The (15S)-15 methyl and 16, 16 dimethyl analogues were 40 times as active as prostaglandin E2 in inhibiting pentagastrin-stimulated acid secretion on intravenous administration to the anaesthetized rat, and 100 times as active on subcutaneous injection to the chronic fistula rat. 3 In antisecretory doses, the analogues, like prostaglandin E2, caused bile reflux and, in higher doses, profuse diarrhoea. 4 The (15S)-15 methyl and 16, 16 dimethyl analogues were at least 30 times as active as prostaglandin E2 in causing changes in intestinal intraluminal pressure in vivo, but were equipotent on isolated smooth muscle. 5 In equivalent antisecretory doses, the methyl analogues had little effect on systemic arterial blood pressure and resting mucosal blood flow compared with prostaglandin E2. 6 The (15R) methyl epimer administered parenterally had little effect on gastrointestinal function but brief acid incubation greatly increased its activity.

Mössbauer Spectra, Bonding, and Structure In Sn(IV) Acetylacetonates

119Sn Mössbauer spectra have been recorded for sixteen acetylacetonates of the type R2–xClxSnL2 (R=Me, Ph; L=anions of acetylacetone or substituted acetylacetone) and Cl4SnHL. The quadrupole splittings have been used to assign stereochemistry for most of these compounds. The good correlation between quadrupole splitting and center shift for the dimethyl analogues shows that there is no appreciable Sn 5s character in the Sn—L bonds. The correlation between [Formula: see text] and center shift for the dimethyl compounds is consistent with the above interpretation, and indicates that changes in [Ψ(0)5s]2 are dominant in determining both the center shift and J values for these compounds. The Mössbauer parameters for the compounds containing a neutral ligand show that the bonding properties of HL are very similar to those of L.The dimethyl compounds all show a pronounced Goldanskii–Karyagin asymmetry in their spectra. The direction of this asymmetry is shown to be consistent with a positive quadrupole splitting for all the dimethyl compounds.

The insecticidal activity of diethyl and dimethyl analogues of azinphos, bromophos, carbophenothion and parathion on glass surfaces and in soil

AbstractThe insecticidal activity of dimethyl and diethyl forms of parathion, carbophenothion, bromophos and azinphos on glass surfaces and in soil was assessed by bioassay with adult vestigial winged Drosophila melanogaster (Meig.). Both on glass and in soil there were large differences in the initial toxicities of the four different pairs of insecticides, but little difference between diethyl and dimethyl forms of each compound. In soil, toxicity was influenced greatly by soil type and moisture content, decreasing in the order moist sand = dry sand > moist clay‐loam > dry clay‐loam > dry peat > moist peat. Some of these effects may have been caused by differences in the behaviour of insects confined with moist or dry treated soils.In sterilised or unsterilised moist clay‐loam, diethyl forms of three of the four compounds remained toxic longer than their dimethyl counterparts. Possibly such differences could account for the greater effectiveness of certain diethyl compounds in field control of soil insect pests.

Intermediates in the decomposition of aliphatic diazo-compounds. Part VIII. The mechanism of ether formation from diarylmethylenes and alcohols

The thermal decomposition of diphenyldiazomethane and its 4,4′-dichloro-, 4,4′-dimethoxy-, and 4,4′-dimethyl analogues at 85 °C in acetonitrile containing methyl and t-butyl alcohols (ca. 1M) has been studied. Kinetic studies indicate that the major reaction product, the alkyl diarylmethyl ether, is formed by attack of intermediate diarylmethylene on the alcohol. The relative reactivities of methyl and t-butyl alcohols towards the series of diarylmethylenes have been determined: methyl alcohol is the more reactive in all cases, but the difference in reactivity between the two alcohols decreases with increasing electron release by the 4-substituents. By examining the radioactivity of the product ethers formed by reaction of diarylmethylenes with hydroxyl-tritiated alcohols, substantial kinetic isotope effects on ether formation have been detected. The isotope effects are in all cases greater for formation of t-butyl ethers than for methyl ethers. The compatibility of these observations with three possible mechanisms of ether formation has been assessed, and it is concluded that the most likely route is that in which the carbene attacks the oxygen atom of the alcohol to form an ylid which is subsequently transformed by a prototropic rearrangement into the ether.

Specificity and control of choline-O-sulfate transport in filamentous fungi.

Choline-O-sulfate uptake by Penicillium notatum showed the following characteristics. (i) Transport was mediated by a permease which is highly specific for choline-O-sulfate. No significant inhibition of transport was caused by choline, choline-O-phosphate, acetylcholine, ethanolamine-O-phosphate, ethanolamine-O-sulfate, methanesulfonyl choline, 2-aminoethane thiosulfate, or the monomethyl or dimethyl analogues of choline-O-sulfate. Similarly, no significant inhibition was caused by any common sulfur amino acid or inorganic sulfur compound. Mutants lacking the inorganic sulfate permease possessed the choline-O-sulfate permease at wild-type levels. (ii) Choline-O-sulfate transport obeyed saturation kinetics (K(m) = 10(-4) to 3 x 10(-4)m; V(max) = 1 to 6 mumoles per g per min). The kinetics of transport between 10(-9) and 10(-1)m external choline-O-sulfate showed that only one saturable mechanism is present. (iii) Transport was sensitive to 2,4-dinitrophenol, azide, N-ethylmaleimide, p-chloromercuribenzoate, and cyanide. Ouabain, phloridzin, and eserine had no effect. (iv) Transport was pH-dependent with an optimum at pH 6. Variations in the ionic strength of the incubation medium had no effect. (v) Transport was temperature-dependent with a Q(10) of greater than 2 between 3 and 40 C. Transport decreased rapidly above 40 C. (vi) Ethylenediaminetetraacetate (sodium salts, pH 6) had no effect, nor was there any stimulation by metal or nonmetal ions. Cu(++), Ag(+), and Hg(++) were inhibitory. (vii) The initial rate at which the ester is transported was independent of intracellular hydrolysis. After long periods of incubation (> 10 min), a significant proportion of the transported choline-O-sulfate was hydrolyzed intracellulary. In the presence of 5 x 10(-3)m external choline-O-sulfate, the mycelia accumulated choline-O-sulfate to an apparent intracellular concentration of 0.075 m by 3 hr. Transport was unidirectional. No efflux or exchange of (35)S-choline-O-sulfate was observed when preloaded mycelia were suspended in buffer alone or in buffer containing a large excess of unlabeled choline-O-sulfate. (viii) The specific transport activity of the mycelium depended on the sulfur source used for growth. (ix) Sulfur starvation of sulfur-sufficient mycelium resulted in an increase in the specific transport activity of the mycelium. This increase was prevented by cycloheximide, occurred only when a metabolizable carbon source was present, and resulted from an increase in the V(max) of the permease, rather than from a decrease in K(m). The increase could be partially reversed by refeeding the mycelia with unlabeled choline-O-sulfate, sulfide, sulfite, l-homocysteine, l-cysteine, or compounds easily converted to cysteine. The results strongly suggested that the choline-O-sulfate permease is regulated primarily by repression-derepression, but that intracellular choline-O-sulfate and cysteine can act as feedback inhibitors.

Alicyclic and heterocyclic carbamates

The development of heterocyclic carbamates with insecticidal activity is illustrated. The variation of compounds with a repellent effect range from aromatic amides to carbamates with pronounced insecticidal properties. Enolisable heterocyclic compounds, based on 3-methyl-pyrazolon or hydroxy-pyrimidine, were tested, and dimetilan (2-dimethylcarbamoyl-3-methylpyrazolyl-5-dimethylcarbamate) with strong stomach poison activity against houseflies, and PyramateR (2-n-propyl-4-methyl-pyrimidyl-6-dimethyl-carbamate) with a good contact activity against houseflies and a low toxicity for warm-blooded animals, were developed. The synthesis and purification of these two compounds led under certain conditions to isomers. A comparison of the insecticidal and toxicological properties is given. The insecticidal activity of a further class of carbamates (1-alkylthio-methyl-3-methyl-pyrazolyl-5-dimethylcarbamates) is specified. For this type of compound, isomers with differences in activity and toxicity were obtained. A further class of compounds of low mammalian toxicity is obtained by condensation of 3-methyl-pyrazolyl-5-dimethylcarbamate with esters of the acrylic acid: they have a pronounced effect on Diptera and Homoptera. More favourable lack of toxicity toward warm-blooded animals combined with a good insecticidal activity was observed in monomethylcarbamates compared with the corresponding dimethyl analogues, but the monomethylcarbamates proved to be much more susceptible to hydrolysis. The search for new compounds without this disadvantage led to other carbamates, i.e. those of the quinolines, from which GS 13798 is so far the most noteworthy representative. Despite its rather narrow spectrum, it has outstanding activity against sensitive and resistant cockroaches.

KINETIC STUDIES ON TRANSPORT OF PAH AND OTHER ORGANIC ACIDS IN ISOLATED RENAL TUBULES.

Studies were made on the uptake and washout of PAH and other organic acids in isolated renal tubules and cells at 25 C. The renal tubules accumulated PAH rapidly in the first 30-min period. Probenecid, its diethyl- and dimethyl analogues, hippuric acid, and 2,4-dinitrophenol inhibited the tubular transport of PAH competitively. A relationship between the inhibitory effect and the partition coefficient of the compound was observed; the higher the partition coefficient, the greater the inhibition. DNP was also accumulated in the isolated renal tubules. This accumulation was depressed by probenecid, indicating that DNP is probably transported by the same tubular transport mechanism for PAH and other organic acids. In washout experiments probenecid and DNP showed a biphasic action, namely, they stimulated the PAH washout in low concentration and inhibited it in high concentration However, hippuric acid, which has a low partition coefficient, demonstrated an augmentation of PAH washout even at a concentration of 2 x 10–2 m

Selective Insecticidal Action of Isopropyl Parathion and Analogues

The comparative susceptibility of honey bees, Apis mellifera L., and house flies, Musca domestica L., to a series of substituted phenyl dialkyl phosphorothionates was investigated by topical applications. The p -nitrophenyl diisopropyl phosphorothionate (isopropyl parathion) was only about 0.005 as toxic to the bee as to the fly, although the corresponding dimethyl, diethyl, and dipropyl analogues were nearly equitoxic to both species. Similar selectivity associated with isopropyl esters was demonstrated for several other series of phosphorothionate compounds. The biochemical basis for this selectivity was studied. The lowered activity of isopropyl parathion to the bee appears to be the overall result of a decreased rate of in vivo oxidation to the lethal p -nitrophenyl diisopropyl phosphate together with a decreased affinity of this latter compound for bee cholinesterase.

The N-alkyl group specificity of cholinesterase from the housefly, Musca domestica L., and the two-spotted spider mite, Tetranychus telarius L.

Seventeen N-alkyl substituted analogues of acetylcholine were tested as substrates for cholinesterase from housefly head and two-spotted spider mite. The housefly enzyme hydrolyzed the dimethyl and diethyl alkyl analogues rapidly whereas the activity to the dipropyl and dibutyl alkyl ester was low. With the mite enzyme no clear pattern of specificity to the esters was obtained. The propylene and butylene analogues of acetylcholine were hydrolyzed differently by the enzyme from the two sources.