Physostigmine pharmacology

The miotic effect induced by physostigmine lends itself to investigation of the interrelation of chemical constitution and pharmacological action, and Stedman has devoted much attention to this subject. Eseroline is devoid of miotic activity, so that the latter action in physostigmine must be mainly due to the fact that it is a methylurethane, and, since activity only becomes evident in the urethanes of phenolic bases or phenols with a basic side-chain, a basic nucleus for the urethanes appears also to be essential. 

The effect of anisodine (91) on the release of acetylcholine has been investigated (211-213). Investigation of the pharmacological effects of anisodine (91) on the central nervous system in rabbits has shown a strong depressant effect (210). The effect was antagonized by physostigmine and... 

Kleinwaehter enthusiastieally reeommended that other physieians, if ever eonfronted by belladonna toxieity, use Calabar extraet (physostigmine). His report, however, never made it into Ameriean textbooks of olinieal pharmacology. A few late 19" eentury publieations by other authors mentioned physostigmine s effieaey, but thereafter it faded into relative oblivion until the resourceful Sp-5 Goodman unearthed and translated the story. 

Reversible cholinesterase inhibitors form a transition state complex with the enzyme, just as acetylcholine does. These compounds are in competition with acetylcholine in binding with the active sites of the enzyme. The chemical stracture of classic, reversible inhibitors physostigmine and neostigmine shows their similarity to acetylcholine. Edrophonium is also a reversible inhibitor. These compounds have a high affinity with the enzyme, and their inhibitory action is reversible. These inhibitors differ from acetylcholine in that they are not easily broken down by enzymes. Enzymes are reactivated much slower than it takes for subsequent hydrolysis of acetylcholine to happen. Therefore, the pharmacological effect caused by these compounds is reversible. 

Ohno M, Kishi A, Watanabe S Effect of cholinergic activation by physostigmine on working memory failure caused in rats by pharmacological manipulation of hippocampal glutamatergic and 5-HTergic neurotransmission. Neurosci Lett 217 21-24, 1996... 

The pharmacological actions of physostigmine are similar to those of cholinergic drugs. Topical instillation into the eye produces miosis, spasm of accommodation and decrease in intraocular pressure. Physostigmine is well absorbed after oral as well as parenteral administration and also produces central cholinergic actions because of penetration into blood brain barrier. 

The first examples of asymmetric Heck cyclizations that form quatemaiy carbon centers with high enantioselectivity came from our development of an asymmetric synthesis of the pharmacologically important alkaloid (—)-physostigmine (184) and congeners (Scheme 6-31) [68]. In the pivotal reaction, (Z)-2-butenanilide iodide 182 was cyclized with Pd-(5)-BINAP to provide oxindole 183 in 84% yield and 95% ee after hydrolysis of the intermediate silyl enol ether. With substrates of this type, cyclizations in the presence of halide scavengers took place with much lower enantioselectivity [68]. 

Mewaldt, S. P., Ghoneim, M. M. (1979). The effects and interactions of scopolamine, physostigmine and methamphetamine on human memory. Pharmacology Biochemistry and Behavior, 10, 205-210. 

Wenger, G. R. (1979). Effects of physostigmine, atropine and scopolamine on behavior maintained by a multiple schedule of food presentation in the mouse. Journal of Pharmacology and Experimental Therapeutics, 209, 137—143. 

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