AbstractDurch Umsetzung der Indole (I) mit Glyoxylchlorid (II) und Piperazin (III) werden die Bis‐glyoxylamide (IVa) und durch nachfolgende Reduktion die Titelverbindungen (IVb) synthetisiert.

Abstract Five procedures have been used to compare the pharmacological effects and time-activity profiles of anti-acetylcholine drugs in the central and peripheral nervous system (ens, pns). In particular, the potencies of optically pure enantiomers of anti-acetylcholine drugs which contain an asymmetric centre have been determined. The following four observations are made which are of relevance to all studies of anti-acetylcholine drugs. (1) Times to onset of activity of anti-acetylcholine drugs in three in vivo tests and the duration of action in one in vivo test are shown to increase as affinity constants, determined in vitro, increase. (2) Below a dose of ca 0.03 μmol kg−1no anti-acetylcholine drug produces maximum mydriatic effects and all anti-acetylcholine drugs which have log affinity constant values >9.49 produce maximal effects at approximately this dose. (3) The receptor with which anti-acetylcholine drugs interact is essentially the same in the eye, salivary gland and ens of the mouse, the guinea-pig ileum, and in the cat ens. (4) For any anti-acetylcholine drug the time to onset of effects in the ens is similar to the time of onset of effects in the pns and appears to depend on the affinity constant rather than on the partition properties of the drug. The practical and theoretical significance of these and other observations are discussed.

Abstract Measurements of neuromuscular blocking and antimuscarinic activity have been made in a series of bis-atropinium (BA) and N-n-alkyl atropinium (N-AA) compounds. That the second atropinium group contributed to the neuromuscular blocking activity of BA compounds was shown by the relative lack of such activity in the N-AA series of compounds. Peak neuromuscular blocking activity occurred when two atropinium groups were separated by a chain of either 10 or 11 methylene groups. Members of both series of compounds displayed antimuscarinic properties but estimates of activity differed according to whether they were obtained by determination of affinity constants on guinea-pig isolated ileum or production of mydriasis in mice. From measurements of affinity constant on the guinea-pig ileum it is concluded that BA compounds interact with only one muscarinic receptor. However, the high activity of the deca- and undecamethylene BA compounds in producing mydriasis suggest that these compounds possibly interact with two receptors at once.

Abstract Some diastereoisomeric dimethylaminobornyl acetates and their methiodides have been prepared and tested for ganglion blocking activity. Included in these compounds was an enantiomeric pair and associated quaternary salts. These optical antipodes displayed virtually no difference between their actions at the ganglion. Differences between the activities of the least and most potent diastereoisomers was limited to a factor of about five. Assays were made upon the cat superior cervical ganglion and also the guinea-pig vas deferens preparation the successful quantitative use of which is described.

Abstract The anti-acetylcholine potencies of the dimethylaminoethyl and N/-methyl piperidin-4-yl esters of R and S 2-cyclohexyl-2-hydroxy-2-phenylacetic acid and their quaternary derivatives have been measured by in vitro and in vivo procedures. The R-enantiomer of dimethylaminoethyl-2-cyclohexyl-2-hydroxy-2-phenylacetate was approximately 100 times more active than the corresponding S-enantiomer both in vivo and in vitro. In contrast, the differences in potencies of the enantiomers of the other compounds were smaller in vivo than in vitro and moreover, the in vivo differences in potency decreased as the potency of the racemates increased. The relevance of these results to general studies of enantiomeric differences is discussed.

Triflupromazine was found to potentiate the actions of six anticholinergic drugs in producing elevation of EEG arousal thresholds, and dissociation between EEG and behavioural arousal thresholds, in cat encéphale isolé preparations. The effects of triflupromazine on the anticholinergic activity of the six drugs were studied using as tests antagonism of oxotremorine-induced salivation and tremors and production of mydriasis in mice.

1. The central and peripheral anticholinergic activities of a series of drugs comprising atropine, hyoscine, caramiphen and one of its analogues, and three glycollic acid esters, have been measured.2. The ability of the same drugs used alone, and in conjunction with N-methyl pyridinium-2-aldoxime methanesulphonate (P2S), to protect mice, rats and guinea-pigs from the lethal effects of sarin has been assessed.3. No correlation was found to exist between central or peripheral anticholinergic activity and ability to protect from sarin.4. On the indirectly stimulated isolated rat phrenic nerve-diaphragm preparation all drugs with the exception of hyoscine caused potentiation of responses to low frequency stimulation but partial block of responses to high frequency stimulation. The drugs did not reverse the effects of sarin on the phrenic nerve-diaphragm preparation.6. It is concluded that a pharmacological action other than an anticholinergic one is involved, in part, in the protective actions against sarin of some of the drugs studied. Whether their effects on skeletal muscle are of any relevance in this respect is unresolved.