Muscarinic properties of compounds related to arecaidine propargyl ester

A series of new analogues of the arecaidine propargyl ester (CAS 35516-99-5), APE, 1a) with alcohols consisting of 4 or 5 carbon atoms were investigated at muscarinic receptor subtypes. The muscarinic activity of the quaternary and tertiary salts of the APE-related compounds were assayed on the isolated guinea-pig ileum (M3 receptor subtype) and guinea-pig left atria (M2 receptor subtype) as well as on rabbit isolated vas deferens (M1 receptor subtype). The structural variations made in the APE molecule, replacing the triple bond in the ester side chain with structures such as double bond, an allene moiety, a single bond, a cyclopropyl group or two triple bonds should alter the selectivity and potency in favour of the M2 subtype. Enhanced, though modest, selectivity for M2 receptors was achieved with the 2-butynyl ester 2a. The other structural variations resulted in a loss of potency, but not necessarily of efficacy.     

Physicochemical properties and biological activity: Thermodynamic properties of compounds related to acetylcholine assessed from depression of freezing-point and enthalpies of dilution

1 Measurements have been made of the osmotic coefficients and enthalpies of dilution of acetylcholine and of compounds related to it in which the carbonyl and ether groups have been replaced by methylene and the trimethylammonium group by triethylammonium. All were iodides. Measurements were also made with tetraethylammonium iodide and agree with published values.     

An attempt to study the effects of chemical structure on the affinity and efficacy of compounds related to acetylcholine

Two sets of series of compounds, RN⁺Me₃, RN⁺Me₂Et, RN⁺MeEt₂, RN⁺Et₃, and R'N⁺Me₃, R'N⁺Me₂Et, R'N⁺MeEt₂, R'N⁺Et₃, have been prepared, in which R is a 2-(diphenylacetoxy)ethyl, 2-(benziloyloxy)ethyl, 2-(2,2-diphenylethoxy)ethyl, 3-(diphenylmethoxy)propyl or 3,3-diphenylbutyrylmethyl group, and R' is a 2-acetoxyethyl, 2-ethoxyethyl, 3-methoxypropyl or butyrylmethyl group: compounds of the first set therefore differ from those of the second set in that they contain a diphenylmethyl group (or a benziloyl group) in place of a methyl group. The former compounds are antagonists of acetylcholine whereas most of the latter act like acetylcholine. The affinity constants of the former compounds for the acetylcholine receptors of the guinea-pig ileum have been determined and the equipotent molar ratios relative to acetylcholine have been measured for the latter compounds. The variation of the affinity constant with the constitution of the onium group in the antagonists (the diphenylmethyl compounds) was sufficiently consistent from one series to another for it to seem likely that corresponding changes in affinity with the constitution of the onium group would occur in the agonists. From the relative activity of the agonists and with this knowledge of relative affinity it was possible to assess the effects of their structure on efficacy. Substitution of one methyl in the onium group by an ethyl group in these compounds increased affinity but decreased efficacy. The replacement of a second methyl by a second ethyl group had little effect on affinity but decreased efficacy still further. The replacement of the ester link in acetylcholine by a 4-ether oxygen atom (as in the diphenylmethoxypropyl and methoxypropyl compounds) did not appreciably reduce affinity but markedly reduced efficacy, whereas the replacement of the ester link by a 3-ether oxygen atom (as in the diphenylethoxyethyl and ethoxyethyl compounds) markedly reduced affinity but did not reduce efficacy. The diphenylbutyrylmethyl compounds had low affinity and the butyrylmethyl compounds had low efficacy. We conclude that the action of acetylcholine at the postganglionic parasympathetic receptors in the guinea-pig ileum depends upon the presence of the 4-carbonyl group (and presumably the onium group) for affinity and on the 3-ether oxygen atom and the trimethylammonium group for efficacy.     

The effects of acetylcholine on bulbar respiratory related neurones

Summary The effects of cholinergic agonists and antagonists applied by microiontophoresis to bulbar respiratory neurones were determined in different preparations: cats anaesthetized by pentobarbital and immobilized by gallamine triethiodide, intercollicular decerebrate cats either not immobilized or immobilized by gallamine triethiodide. Respiratory neurones located at the bulbar level exhibited a muscarinic cholinergic sensitivity in all preparations. Muscarinic responses were either excitatory or inhibitory. The number of neurones showing excitatory responses was lower under pentobarbital anaesthesia than in decerebrate cats.     

Cephalosporin antibiotics. II. Synthesis and biological properties of CS-461 and related compounds

The synthesis, structure-activity relationships, and biological properties of 3-thiazoliomethyl cephalosporins are described. 7-[2-(2-Aminothiazol-4-yl)-(Z)-2- methoxyiminoacetamido]-3-[5-(2-hydroxyethyl)-4-methylthiazoliomethyl+ ++]-3- cephem-4-carboxylate sulfate (CS-461) showed potent antibacterial activity against a wide variety of bacteria both in vitro and in vivo. Furthermore, CS-461 exhibited significantly low acute toxicity in mice.     

与药效有关的小蘗碱物理化学性质的研究 Ⅰ.小蘗碱的酸解常数问题

用光谱法测定了氯化小蘖碱的酸解常数(K_a),在pH 14-15水中pK_a为15.23,在pH 12-13乙醇中pK₂为13.05,和文献所载相差很大.此外并以中性硫酸小蘖碱在氢氧化钡水溶液中,用光谱法测定其季胺离子浓度,未见变化,故可以说明小蘖碱为-强电解质.     

The effects of pentachloronitrobenzene, hexachlorobenzene, and related compounds on fetal development.

Pentachloronitrobenzene (PCNB) containing a number of contaminants produced renal agenesis and cleft palate in $\text{C57B1}\text{6}$ mice, cleft palate in CD-1 mice, but was not teratogenic in CD rats. The major contaminant was hexachlorobenzene (HCB), which produced cleft palates and some kidney malformations in CD-1 mice. Purified PCNB (<20 ppm HCB) showed more maternal toxicity than the contaminated PCNB and resulted in a few cleft palates in the fetuses; there were no kidney malformations with purified PCNB. Thus, the teratogenic activity of contaminated PCNB was probably due to the HCB. Tetrachloronitrobenzene, a contaminant, and pentachloroaniline, a metabolite of PCNB, were not teratogenic in mice or rats. Pentachlorophenol was not teratogenic in rats. Tissue distribution of PCNB, its metabolites pentachloraniline and methyl pentachlorophenyl sulfide, and the contaminants pentachlorobenzene and HCB were studied in pregnant $\text{C57B1}\text{6}$ mice. The tissue distribution of HCB and pentachlorobenzene was studied in pregnant CD-1 mice. Neither PCNB nor pentachlorobenzene accumulated in tissues. This was in contrast to HCB which accumulated in various tissues such as fat, urinary bladder, skin, and thymus.     

Acid-base properties of pristinamycin IA and related compounds.

The pKa values of acid-base equilibria involved in the protonation of pristinamycin IA and its model compound, N-isobutyl-3-hydroxypicolinamide, were determined by UV-visible absorption spectrometry and potentiometric titration. The equilibrium between dipolar ionic and uncharged neutral forms was investigated spectrometrically in methanol-water solutions. With pristinamycin IA, the dipolar ionic form predominated in aqueous solutions buffered to the isoelectric pH. The effects of structure on the ionization constants are briefly discussed.