2,2'-Phthaloyl-,2,2'-isophthaloyl-, and 2,2'-terephthaloylbis[1,1,1-trimethylhydrazinium] dihydroxide, bis(inner salts): synthesis, partition coefficients, toxicity and effect on ganglionic transmission.

2,2'-Phthaloyl-, 2,2'-isophthaloyl, and 2,2'-terephthaloyl-boff++[1,1,1-trimethylhydrazinium] dihydroxide, bis(inner salts) 7, 8, and 9 and their hydrazide and hydrazinium diiodide precursors were synthesized and tested for toxicity and their ability to block sympathetic ganglionic transmission. Only the 2,2'-phthaloyl and isophthaloylhydrazinium diiodides 4 and 5 produced weak inhibition of nerve transmission (35% at 2.15 X 10(-3) M). The inner salts were appreciably less toxic than the hydrazinium diiodides in brine shrimp testing. The log P (log10, chloroform pH 7 buffer system) values of all compounds were determined and those of the inner salts and hydrazinium diiodides were in the range of -3.03 to -3.60.

Phosphorus-nitrogen compounds. 26. Phosphaminimides. 2. 2,2'-Phosphinylidenebis(1,1,1-trimethylhydrazinium) iodide inner salts as agents affecting ganglionic transmission.

The N-2 atoms of phosphorus 2,2-dimethylhydrazides, contrary to a previous report, can be methylated by iodomethane. Treatment of the resulting dihydrazinium iodides with aqueous sodium hydroxide results in mono- instead of didehydroiodination, apparently due to resonance stabilization of the inner salt form. The phosphaminimide products and their hydrazinium iodide precursors blocked sympathetic ganglionic transmission while one dihydrazide intermediate produced potentiation. Brine shrimp testing indicated that conversion of a hydrazinium iodide to an aminimide moiety results in decreased toxicity.

[New cardiovascular acting 2-aryl-2-imidazolinyl-acetic acids. Synthesis and pharmacologic effects]. / Neue kardiovaskulär wirksame 2-Aryl-2-imidazolinyl-essigsäuren. Synthesen und pharmakologische Wirkungen.

The syntheses of new 2-aryl-2-imidazolinyl-acetic acids and esters are reported together with pharmacological results concerning structure-activity relationship. In contrast to the already known but inactive N(1)-alkylated derivatives of 2-arylamino-2-imidazolines the new compounds with an aryl acetic acid substitution in N(1) position of the imidazoline nucleus show the bradykardic activity of the exocyclic alkylated clonidine derivatives such as alinidine. The majority of these new substances reduce blood pressure and heart rate in anesthetized rats significantly with a long duration of action. 2-[2-(2,6-Dichloro-phenylamine)-2-imidazoline-1-yl]-2-(2-thienyl)- acetic acid 8a is the most potent compound. Blood pressure is lowered by 30-40 mmHg and heart rate by 175 beats/min with a duration of action greater than 60 min. The effect is weakened if the thienyl radical is replaced by other heterocycles or if the 2,6-dichlorphenyl group is replaced by a hydrogen atom. The variation of the substituents in the phenyl nucleus shows that the 2,6-dichlorphenyl structure is the optimum substitution pattern, as in the case of clonidine. In the series comprising the 2-[2-(2,6-dichlorphenylamino)-2-imidazoline-1-yl]-2-phenyl acetic acids (8j-8n) the incorporation of different substituents into the phenyl nucleus in the 2-position results in derivates of different activity. The esters 9a-9c show a faster onset of action as compared to the corresponding carboxylic acid 8a. The most interesting effect of compound 8a in normotensive conscious dogs is a strong and long-lasting decrease in heart rate accompanied by a moderate LVP dp/dtmax decrease, weak lowering of blood pressure and slight increase in LVEDP. After blocking beta-receptors by atenolol the compound 8a still reduces heart rate. Results in ganglion-blocked and pithed rats indicate a presynaptic and postsynaptic alpha 2-agonistic effect. A decrease in sympathetic tone as well as an increase in vagal activity in conscious dogs are considered as possible causes for bradycardic activity. Unlike alinidine, however, compound 8a does not affect directly sinus node function. The bradycardic effect of compound 8a which results in a decrease in oxygen consumption is supposed to be the cause of the reduction of infarct size in anesthetized dogs by 28%.

Semisynthetic derivatives of pyrrolizidine alkaloids of pharmacodynamic importance: a review.

Pyrrolizidine alkaloids occur in more than 40 genera. Among these are two important genera, Senecio and Crotalaria, which have been responsible for heavy losses of livestock and poisoning in man due to their hepatotoxicity. Pyrrolizidine alkaloids are also reported to possess a number of other biological activities. Attempts have been made to convert the pyrrolizidine alkaloids to new structures by synthetic modifications. One hundred and twenty semisynthetic compounds were developed and investigated pharmacologically. The range of activity exhibited was hypotensive, local anesthetic, ganglion blocking, neuromuscular blocking and antispasmodic. The five most promising compounds of these series were subjected to detailed pharmacological investigations.

Nonclassical nicotine antagonists.

A series of "nonclassical" nicotine antagonists was synthesized and compared to the "classical" nicotine antagonist, hexamethonium, by means of the isolated guinea pig atria preparation. 2 was found to be the most potent, followed by hexamethonium and the other antagonists. With the exception of 5, the bisquaternary compounds 1-3 and 7-9 were found to be more potent than the monoquaternary compounds 4, 6, and 10-12. Within a series of compounds (1-6 or 7-12), those compounds possessing two phenyl rings proved to be more potent than those possessing one or three phenyl rings. These and other aspects of the structure-activity relationship of this class of compounds are discussed.

The specificity of some agonists and antagonists for nicotine-sensitive receptors in ganglia.

1 The guinea-pig isolated ileum has been used to estimate the ability of substituted phenylalkylonium salts (related to nicotine) to stimulate or block receptors in ganglia. The effects of hexamethonium were used to indicate which were the most specific ganglion stimulants; these were tested on the blood-pressure of pithed rats and for neuromuscular blocking activity on the rat diaphragm preparation.2m-Hydroxyphenylpropyltrimethylammonium and 3,4-dihydroxyphenethyltrimethylammonium (coryneine, ;quaternary dopamine') were the most active and specific ganglion stimulants but their usefulness in vivo may be limited by their neuromuscular blocking activity. The analogous tertiary compounds are being investigated.3 The affinities of substances which were blocking agents at ganglionic receptors were measured on the isolated ileum with m-hydroxyphenylpropyltrimethylammonium as agonist. The affinities of selected compounds for postganglionic receptors were measured in experiments on the ileum in the presence of hexamethonium and with carbachol as agonist. Some of the compounds were tested for neuromuscular blocking activity on the rat diaphragm.4 Phenylbutyldiethylamine had ganglion-blocking activity greater than pempidine and little postganglionic blocking or neuromuscular blocking activity. Its triethylammonium analogue had higher ganglion-blocking activity but had appreciable neuromuscular blocking activity.5 The aromatic ring system is not essential either for activity or affinity and the effects of substituents are not related to their effects on electron distribution. Stimulant activity is enhanced only by hydroxyl or amino groups in suitable positions; it is not improved by the presence of rigid features (double or triple bonds or a cyclopropane ring) in the side chain. Affinity is slightly increased by chloro or bromo groups in suitable positions but the unsubstituted compounds are among those with the highest affinity. Substituents have similar effects on affinity for postganglionic receptors, though for these receptors the compounds mostly have only about one-tenth of their affinity for ganglionic receptors.