Myotic

Furthermore, in the particular type of phosphate molecule under discussion (VI) we showed that when X is fluorine, compounds of high toxicity result whereas myotic effect is absent and toxicity of a low order if X = H, Et, OH, OEt, OCH2CH2C3, OCH2CH2F, Cl, NH2, NHMe, NHPh, CH2CH2F, CN, SON, etc.1 In Chapters rv and vi, however, we consider in more detail cases where X is not fluorine, but nevertheless toxicity results. Toxicity is also of a low order in the aromatic series for example, diphenyl phosphorofluoridate is relatively non-toxic and devoid of myotic properties. We also showed that ethyl phosphoro-difluoridate, (C2H50)P0F2, had neither myotic nor toxic action.1... 

Many of these compounds were toxic for example, tetra-methyl phosphorodiamidic fluoride (dimethylaminofluorophos-phine oxide (VII)) had a l.c. 50 of 0-1 mg./l. Unlike the phosphorofluoridate esters, however, they were devoid of myotic action. 

Among many esters, di w propyl and diisopropyl phosphoro-fluoridate were prepared by the action of phosphorus oxy-dichlorofluoride on ra-propyl and isopropyl alcohol respectively. The n-ester was less toxic and possessed only feeble myotic... 

The above proof of the extremely high affinity for cholinesterase of the phosphorofluoridates, especially those with branched-chain alkyl groups, suggested that the toxic and myotic power was due to inhibition of cholinesterase in vivo. Bloch1 showed... 

Effect on the eye. Leopold and Comroe4 recorded the actions of D.F.P. on the normal eye, expanding the earlier British work (pp. 2, 43). They confirmed the prolonged myosis lasting up to 3 weeks with a spasm of the ciliary muscle for 3-7 days. There is usually a decrease in the intra-ocular tension, although occasionally there may be a slight rise before a fall in pressure. The action outlasts that of common myotics, and a 0-1 per... 

Structural Requirements for High Toxicity and Myotic Action of Esters of Phosphorofluoridic Acid... 

We found that the toxicity and myotic activity of di-isopropyl phosphorofluoridate (XI) were far greater than that of di- propyl phosphorofluoridate. In Report no. 6 on fluoro-phosphonates to the Ministry of Supply3 we described the preparation of di aec.-butyl phosphorofluoridate (XII) by the hydrogen phosphite method (p. 6). The compound was found to be very toxic and to produce severe myosis in man and animals. The symptoms displayed during and after exposure were identical with those produced by di-isopropyl phosphorofluoridate. The L.c. 50 for di-sec.-butyl phosphorofluoridate for mice for deaths within 2 hr. was 0-6 mg./l., and that for deaths within 48 hr. was 0-54 mg./l. 

In view of the high toxicity and very pronounced myotic effect of di-isopropyl phosphorofluoridate, di ( 1 Z dichlorowo propyl) phosphorofluoridate (XVI) was of special interest. It was prepared from l 3-dichlorohydrin and phosphorus trichloride. It did not have any appreciable myotic effect and the toxicity was of alow order. Di ( 1 -ethylpropyl) phosphorofluoridate (XVII),... 

Discussion. From the investigations of the compounds described so far, it is evident that the myotic effect and toxicity of the molecule POX(0 CH-fti2 )2 depend upon the nature of X, B and B. In this particular type2 of molecule if X is fluorine, then high toxicity and myotic properties result. Myotic effect is absent and toxicity is of a low order if X = H, Et,... 

In the molecule (X = F), the pupil-constricting action and toxicity are increased by a secondary grouping (e.g. R=R = Me . R = Me, 72 = Et RR = cycZohexyl R = Me, R = CH2 CHMe2). Furthermore, it appears that for non-cyclic compounds both R and R, for the best results, must be unsubstituted hydrocarbon radicals (e.g. if R = Me and R = C02Et the compound is scarcely toxic). Similarly, if R =. S = CH2C1, both the myotic effect and toxicity are of a low order. Among unsubstituted (non-cyclic) secondary radicals, the best results seem to be obtained when one group, at least, is Me for example, if. R =. R = Et, the toxicity is considerably reduced. 

Turning again to primary phosphorofluoridates (R = H), if R is substituted, e.g. in di-(2-chloroethyl) phosphorofluoridates, the toxicity and myotic effect are greatly inferior to those shown by the unsubstituted diethyl phosphorofluoridates. Toxicity is also very low in the aromatic series for example, diphenyl phos-phorofluoridate is non-toxic and devoid of myotic properties. Similar remarks apply to certain sulphur analogues, e.g. diethyl phosphorofluoridodithiolate, POF(SEt)2 (preparation, p. 54). 

The myotic, toxic and other physiological properties of the dialkyl phosphorofluoridates, POF(O.R)2, have been fully described on pp. 42, 68 et seq. In 19444 we described an analogous compound of the phosphorofluoridite series, namely, diethyl phosphorofluoridite, PF(OEt)2. This could not be prepared by the action of sodium fluoride on the corresponding diethyl phosphorochloridite (the preparation of which is considered below). We obtained it, however, by the action of ethyl alcohol on phosphorus dichlorofluoride,... 

It was found that tetramethylphosphorodiamidic fluoride (bisdimethylaminofluorophosphine oxide) was very toxic and had a l.d. 50 of the order of 1-0 mg./kg. for subcutaneous injection into mice the concentration for rabbits was higher at 3 0 mg./kg. (intravenously). The Cambridge figure for toxicity by inhalation agreed with that found by American workers, the L.c. 50 for mice being 0 095 mg./l. for a 10 min. exposure. We also carried out experiments with four human observers exposed to a concentration of one part in a million for 5 min. No effects of any kind were noted in particular, myotic action was absent. In this report, therefore, the highly toxic compound... 

II) differed markedly from the toxic di-isopropyl phosphoro-fluoridate (IV), in that the latter showed powerful myotic action. It is to be noted also that, whereas (IV) caused 50 per cent inhibition of cholinesterase activity at a concentration of the order of 10 10 M, a concentration of ca. 8 x 10 5 M of (II) was necessary to produce the same percentage inhibition.2... 

In view of the rapid toxic action and myotic effect of the dialkyl phosphorofluoridates and of the high toxicity of some of the phosphorodiamidic fluorides, we prepared2 and examined a hybrid molecule containing the essential features of each type of compound. The first to be examined was ethyl phenyl-phosphoramidofluoridate (VII). One mol. of phosphorus oxy-dichlorofluoride was added to 1 mol. of ethyl alcohol, and the resulting ethyl phosphorofluoridochloridate (which it was not necessary to isolate) was treated with aniline. 

Ethyl dimethylphosphoramidofluoridate (VIII) was prepared by a similar method and proved to be a very toxic liquid. Its l.d. 50, on intravenous injection into rabbits and also on subcutaneous injection into mice, was 2-5 mg./kg. Toxicity was also determined by inhalation and a Ct ((7 = concentration, <=10 min.) of 200 mg./min./cu.m. killed seven out of a batch of eleven rabbits, guinea-pigs, rats and mice a Ct of 100 mg./min./cu.m. killed four out of eleven. The compound also possessed myotic properties. Other compounds that we made in this series were much more toxic and it will be seen that they bear some resemblance to tabun and sarin now about... 

In Chapter rv we have described toxic fluorine1 compounds containing the >POF grouping. Such compounds possessed quick knock-out action, and many of them were powerful myotics. Compounds of the fluoroacetate series are characterized by the CH2F- group. Many of them are highly toxic with delayed action, but are completely devoid of myotic activity. The action is, broadly speaking, that of a convulsant poison (but see p. 136). 

The ester must in addition contain some group which will initiate the approach of the ester to the surface of the enzyme. In this connexion it should be noted that di-isopropyl phos-phorochloridate (III, X = Cl), in which the chlorine atom is chemically very reactive,3 has no toxic properties, is devoid of myotic and anti-cholinesterase activity. In this compound, the chlorine is hydrolysed very quickly in water and would probably be destroyed extremely quickly in vivo. We have shown, quite conclusively, that in non-polar solvents the phosphorochloridate... 

Pilocarpine acts by stimnlating mnscarinic receptors, therefore making it similar in action to acetylcholine when systematically introduced. This compound differs from acetylcholine in that it does not react with any nicotinic receptors, but by stimulating the CNS. Its effects are blocked by atropine. It has found therapeutic use in ophthalmology as a myotic agent. Synonyms are pilopine, isopto carpine, and atmocaprine. 

Harima, T., et al. 1986. Enhancement of the myotic response of rabbits with pilocarpine-loaded polybutylcyanoacrylate nanoparticles. Int J Pharm 33 187. 

Rutaceae) gastric, salivary lachrymal secretory stimulant, myotic, parasympathomimetic]... 

Carbachol (= Carbamyl Synthetic mACh-R agonist [cholinergic, myotic,... 

Neostigmine (= 3-Dimethyl-carbamoxyphenyl) trimethylammonium] (quaternary amine aryl carbamate) Synthetic - cf. Physostigmine AChE (carbamoylates - forms carbamoyl ester with active site Serine) [cholinergic, myotic, toxic (curare antidote)]... 

Pilocarpine is a widely studied peripheral stimulant of the parasympathetic system (101). It is used topically as a myotic to counteract the mydriatic effect of atropine and other parasympatholytic drugs. It has clinical value in the treatment of glaucoma when used as eye drop solutions ranging from 0.5 to 10% in concentration (102). Pilocarpine is reported to stimulate the growth of hair and therefore was employed in hair lotions (1). Internally, it was used as a diaphoretic in the treatment of nephritis (103). 

The chemical structure of baogongteng A (1), a new myotic agent from Erycibe obtusifolia, has been determined. High-resolution mass-spectral data indicated the presence of a 3,6-disubstituted tropane skeleton. Infrared and and n.m.r. data indicated the presence of secondary amine, secondary hydroxyl, and acetoxy functions, and the location of the latter group at C-6 was based on comparison of n.m.r. chemical shifts with those of 6B-acetoxy-3a-tropanol. The hydroxyl group was assigned to the 23-position from the n.m.r. spectrum of the N-methylated alkaloid. 

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