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Cyclopentolate

DaMocles-SS2018- Franziska Schmitt, René Steinbrecher, Lisa Steuernagel, Christina Strobel- Hofmann

1. Introduction Cyclopentolate is used as the hydrochloride in common medication that dilates the pupillary constrictor muscles by blocking para sympatholytic receptors in the iris and . It is a mydriatic, that prevents the eye from to different distances, what is called . So it takes place in pediatric eye examinations or to help the eye to cure a ophthalmitis by sedating it.

It makes the eye losing the focus, but very rarely it can make the patient losing its focus too as a symptom of intoxication.

In very less cases the use of Cyclopentolate can cause acute psychoses, that goes with strong symptoms of intoxication like disorientation, incoherent speech, visual and acoustic and sometimes aggressive behavior.

This can persist for 10 to 24 hours or longer but does not harm the patient chronically.

2. Chemical Structure and Physical Characteristics

Fig. 2 Structure of Cyclopentolate

Let’s take a closer look at the physical characteristics and the chemical structure.

The UPAC-name is: (R/S)2-(dimethyleamino)ethyl2-(1-hydroxy-cyclopentyl)-2-phenylacetate.

It owns the molecular formula C17H25NO3.

The CAS-number is 512-15-2.

It has the molecular weight 291,391g/mol.

The melting point is between 134°C and 136°C The hydrochloride salt, that is often the dosage form for medical use, melts at 139°C.

The solubility of Cyclopentolate in water is 1,5g/ .

The toxicity (oral LD50) in the rat is 4000mg/kg and in the mouse 960mg/kg.

Cyclopentolate is solid by a temperature from 275 K. It shows up as a white crystalline powder.

DaMocles-SS2018 Franziska Schmitt, René Steinbrecher, Lisa Steuernagel, Christina Strobel-Hofmann 1

The molecule contains a hydro furan that connects via acetal to a phenylacetate. The phenylacetate is linked via carboxylic esterification to a dimethyl aminoethyl, that contains a Nitrogen-atom, which is bonded to two methyl- and one ethyl. The ethyl constitutes the binding from the ester to the Nitrogen.

The hydroxy furan-acetal contains a hydroxyl that can donate a hydrogen-bond. Also, the molecule includes four atoms, that can accept hydrogen-bonds. The nitrogen- and both oxygen-atoms possess free electrons in the valence shell, that can accept the hydrogen-bonds.

Besides this Cyclopentolate comes up with an α-stereocenter at the α-carbon-atom. This Carbon- atom has four different substitutes. The first one is the phenyl group. The second is the Carbonyl- group, the third the cyclopentyl- and the fourth the Hydrogen-atom. Because of that the molecule will show up as a racemate, which contains both enantiomers in the same amount.

3. Background Cyclopentolate is a derivative to the natural product .

Atropine is also a racemate. The S-enantiomer is found in plants of the nightshade family and can be extracted from the belladonna for example. After the extraction and the treatment with a leach the racemate is obtained. It contains a which is bonded by a esterification.

Let’s take a closer look at the structure of Atropine.

Fig. 3 Structure of Atropine

It contains the same α-stereocenter at the first carbon-atom. The stereocenter nearly have the same substitutes as the one in Cyclopentolate. The molecule has the same phenylacetate in it like Cyclopentolate. But it does not have a cyclopentyl and a different nitrogen-group bonded to the phenylacetate. The nitrogen-group is called a tropicamide and shows of normally in plants of the nightshades.

Nevertheless, both molecules operate on the human body very similar.

Atropine is used to cause a cyclopedic too. It has a long history. In the past women starts to take Atropine as acosmetics to apply beauty, because it generates big dark eyes. That´s the reason for calling the plant belladonna. But today Atropine is classified as an essential medicine for the world.

DaMocles-SS2018 Franziska Schmitt, René Steinbrecher, Lisa Steuernagel, Christina Strobel-Hofmann 2

The caused mydriatic effect will last longer than the one from Cyclopentolate. Cyclopentolate seems able to replace Atropine as a drug because of the following reasons.

Fig. 4 Picture of the deadly nightshade also known as

4. Medical Use Cyclopentolate is the shorter-acting- antagonist. The mydriatic effect come fast and lasts for 6-12 hours. It is most intensive after half to one hour and strong in the first hours. It is firstly discovered and reviewed by Trevis and Testa in year 1952 as a fast acting and strong mydriatic that shows up without side effects. Therefor it is surely used to medicate young children and adults. Since 1926 there are 26 cases known in which it shows up with a very strong psychoses as symptom of intoxication, without any drug abuse or any disease prehistory in some cases and on very low doses.

That is a quit unusual fact. Due this a couple of medical examinations were conducted. However, they could not find the reason for this strong reaction or for the intoxication symptoms by taking a low doses. Moreover, they ascertain that the side effects show up more often and in a stronger way when patients have blue eyes or bright skin or hair.

Fig. 5 Cyclopentolate in medical use as “Cyclopent*”

DaMocles-SS2018 Franziska Schmitt, René Steinbrecher, Lisa Steuernagel, Christina Strobel-Hofmann 3

The picture below shows the effect of cyclopentolate on the human eye in the right side, compared to the eye in normal mode.

Fig. 6 Effect on the eye of cyclopentolate compared to the normal eye

5. Mode of action The accommodation of the eye and the pupil movement is regulated by acetylcholine receptors type M1 they are normally found in the human brain. Cyclopentolate is inhibin these receptors temporally. It is called competitive inhibition. Cyclopentolate contains a familiar structure to the neurotransmitter acetylcholine, that is the target molecule of the M1-Receptors.

Fig. 7 Structure of acetylcholine. The Target molecule of M1-acetylcholin receptors

Because of this similar structure the receptor cannot differentiate between target molecule and inhibitor, so it is binding the component that is more often.

While cyclopentolate is bonded to the receptor, the receptor is blockaded for the target molecule acetylcholine. Cyclopentolate the inhibitor is released again after a while and leaves the receptor without modifying them.

The M1-acetylcholin receptor is a G- protein-coupled receptor, that means it is transmembrane enzyme-molecule. The N-terminal end of the protein is located outside the cell, the C-terminal is located inside the cell and linked to a GTP-binding Protein. By detecting molecules outside the cell it activates the internal signal transduction insides the cell and permeate the cellular response.

The function of M1-receptors in the human eye is to transduce light signals to the cells in the ciliary muscle to accommodation the pupil. Therefore, the pupil is dilated while the receptor is inhibited by cyclopentolate.

DaMocles-SS2018 Franziska Schmitt, René Steinbrecher, Lisa Steuernagel, Christina Strobel-Hofmann 4

Fig. 8 schematic picture of the human eye

6. Imprint Author: Franziska Schmitt

René Steinbrecher

Lisa Steuernagel

Christina Strobel-Hofmann

Made for: Studienprojekt DaMocles TUD

Publishing year: 2018

7. Reference list [1] https://www.drugbank.ca/drugs/DB00979

[2] http://www.chemie.de/lexikon/Muskarinischer_Acetylcholinrezeptor.html

[3] https://pubchem.ncbi.nlm.nih.gov/compound/2905#section=Pharmacology-and- Biochemistry&fullscreen=true

[4] https://pubchem.ncbi.nlm.nih.gov/compound/2905#section=Top 1

[5] U. Kellner, J.Esser”Akute Psychose durch Intoxikation mit Cyclopentolat“,Klinische Monatsblätter für Augenheilkunde ,194(06),1989, Pages 458-461

[6] https://www.fachinfo.de/pdf/000494

[7] D. M. Gordon, M. H. Ehrenberg”Cyclopentolate Hydrochloride: A New Mydriatic and Cycloplegic Agent”,American Journal of Ophthalmologie, Vol. 38, Issue 6, 1954 Pages 831

DaMocles-SS2018 Franziska Schmitt, René Steinbrecher, Lisa Steuernagel, Christina Strobel-Hofmann 5

[8] S. M: Egashira, L.L. Kish, J. D. Twelker, D. Mutti, K. Zadrik, A. J. Adams „Comparsion of Cyclopentolate versus Tropicamide Cycloplegia in Children“, American Academy of Optometry,Vol. 70 No. 12, 1993, pages 1019-1026 [9] Pharmakologie und Toxikologie – Arzneimittel verstehen, Heinz Lüllmann, Thieme Verlag, 17. Auflage, 2010 [10] https://www.pharmawiki.ch/wiki/index.php?wiki=atropin patienteninfo-service.de/a-z-liste/c/cyclopentolat-alconR-1-augentropfen/ care-vision.de/blog/tollkirsche-augen [11] https://www.patienteninfo-service.de/a-z-liste/a/atropin-posR-05-augentropfen/ [12] https://de.wikipedia.org/wiki/Anticholinergikum drugs.com/cdi/cyclopentolate.html [13] https://en.wikipedia.org/wiki/Cyclopentolate [14] https://de.wikipedia.org/wiki/Atropin [15] https://www.novartis.de/product-list-patient [16] http://apps.who.int/medicinedocs/documents/s16879e/s16879e.pdf

[17] Fig. 1: Made with © 2017 Avogadro Chemistry. Powered by Jekyll & Minimal Mistakes. [18] Fig. 2: moleview.org [19] Fig. 3: https://www.pharmawiki.ch/wiki/index.php?wiki=atropin [20] Fig 4: http://www.weltderwunder.de/artikel/alles-ist-gift-es-kommt-nur-auf-die-dosis- an [21] Fig. 5 https://www.buy-modafinil-uk.com/Generic-Ak-pentolate-Cyclopentolate- Ophthalmic-Solution-Eye-Drops-p-578.html [22] Fig. 6 https://www.google.de/imgres?imgurl=https://upload.wikimedia.org/wikipedia/ commons/2/2e/Anizokoria.JPG&imgrefurl=https://de.wikipedia.org/wiki/Datei: Anizokoria.JPG&h=204&w=852&tbnid=5RAf7Q4krs1bFM&tbnh=110&tbnw=45 9&usg=__H4HmZr3JMranoKyR97w4Vm- gJis=&hl=de&docid=gzuaLGQdxJC4mM [23] Fig. 7 http://de.nextews.com/c4722915/

DaMocles-SS2018 Franziska Schmitt, René Steinbrecher, Lisa Steuernagel, Christina Strobel-Hofmann 6

[24] Fig. 8 https://www.brillen-sehhilfen.de/auge/iris-regenbogenhaut.php

(all websites checked on 20.06.2018)

DaMocles-SS2018 Franziska Schmitt, René Steinbrecher, Lisa Steuernagel, Christina Strobel-Hofmann 7