PACIFIC SOUTHWEST ASSOCIATION OF CHEMISTRY TEACHERS 0
CHEMICAL ASPECTS OF ANTICONVULSANT DRUGS' I. 1. WILKZ Stanford University, Stanford, California
H ~ m o c m m s ,who lived about two thousand four hundred years ago, said the recurrent attacks of epilepsy seemed to him no more supernatural or mysterious than the recurrent chills of malaria. What was stated then still holds true today. Epilepsy, or seizures, is a disease, no more or less mysterious than malaria, pneumonia, or cancer. Due to fear of the unknown, an aura of superstition has surrounded many diseases. The Egyptians occasionally drilled holes in the skulls of epileptic persons so that the evil spirits might escape. As we learn more, the fear disappears, and the stigma of inferiority associated with these ailments is forgotten. A brief mention of the cause of seizures is of value. The nerve cells in the brain send out extremely weak electrical waves of 10 to 100 cycles per second. These waves may be picked up by an instrument called the electroencephalograph. The wave of a normal person is shown in Figure 1A. If a person is subject to seizures his brain waves during an attack show certain irregularities. A classification into three general types of wave patterns has been made ( I ) . If type I is discovered, Figure l B , the patient is said to have "grand mal" seiznres. When an attack occurs, the patient loses consciousness, falls, twitches, and makes chewing motions, etc. The active phase may last from a minute to half an hour. Many famous people had grand ma1 seizures, such as Caesar, Byron, Berlioz, and Paganini, to name a few. I n type 11, "petit mal" seiznres, Figure lC, the patient becomes dazed, seldom for more than a few seconds. After the attack he will resume what he had been doing. These seizures, which are frequent in children, may occur up to hundreds of times a day. Type 111, Figure ID, is a rarer form of epilepsy, known as a "psychomotor" attack. The patient becomes unreasonable, does not know what he is doing, and may become irritable and violent. The painter van Gogh, who suffered from this type of seizure, cut off one of his ears during an attack. Most attacks last only minutes, but they may go on for days. Generally speaking, two broad divisions of epilepsy may be considered. In idiopathic (hereditary) epilepsy, no evidence for seizures can be found by a thorough physical examination. If, however, attacks are
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Based on talks given a t the University of Cslifornia Medical Centers, San Francisco and Las Angeles, California. 'Public Health Service Research Fellow of the National Cancer Institute
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NO. 4, APRIL, 1957
Figun 1. Elretroensaphalo~phTracings of Brain Waves A. n o r m d , 8 , grand ma1 seizures, C, petit ma1 seizures, D. myohornotor attack.
due to an injury to the brain, or a disease of the body, e.g., a common virus disease like meningitis, influenza, mumps, etc., it is called symptomatic epilepsy. Lennox ($a) believes that only about 5% of persons who have hereditary tendency to seizure will actually ever develop seizures. Among these, many would not have had seizures if a combination of idiopathic (hereditary) and symptomatic (acquired) epilepsy had not occurred. Now we may take a closer look a t the brain waves, caused by electric discharges of nerve cells. Certain cells, for reasons as yet unknown, suddenly "overflow" with electric discharge, as if the insulator holding hack the electric charge had disappeared. Neighboring nerve cells are affected in such a fashion that they, too, discharge excessively, and soon a regular chain reaction is in progress. The more extensive this reaction is, the more violent will be the seizure. After a certain timeehas elapsed, the chain reaction stops, and the cells return to a normal discharge level @b). ACTION OF ANTICONVULSANT DRUGS The purpose of anticonvulsant drugs is to prevent the "overflow" of electric charge in nerve cells. In other words, the chemical dams up the electricity within a cell, i.e., keeps the insulation from "going bad." The selection of the drug, i.e., of the proper type of chemical structure, will depend on the frequency and severity of attacks, and treatment should he continuous. This means t,hat. drug therapy, a t this stage of development, is not a cure but a palliative. If properly 199
administered, these drugs may completely eliminate seizures. However, throughout drug administration one must look for possible side effects, ranging from rash and dizziness to liver damage, agrauulocytosis and aplastic anemia. As in the treatment of other diseases, the benefits and drawbacks of each drug must be carefully weighed before administration. Obviously, a drug will be of improved value if its toxicity is low and its specific effectiveness high. In order to determine whether a certain chemical structure will have these most desirable effects, many chemical compounds have been tested, initially on animals (3). This is done by introducing an anti-
convulsant drug into an animal, such as a mouse, and then causing artificial convulsions. An electric current may be passed through the brain of the animal. If the drug will prevent "electroshock" seizures, it may conceivably turn out to be a compound effective in grand ma1 treatment. In the second method, a chemical causing convulsions is introduced into the animal. This chemical is pentamethylenetetrazole, Metrazole. If a compound will be antagonistic to metrazole-produced seizures, it may develop into a drug of value in petit ma1 seizures. So far there is no effective way theoretically to predict, from the exact structure of a chemical compound, whether or not it
TABU 1 Anticonvulsant h u g s Formula and trade name
Chemical name
Useful in the treatment of
Possible side effects
Comments
Referm e
...
...
BARBITURATES
Phenobarbital ( I ) R, = H, R2 = Ph, R, = E t Mebaral(I1) R, = Me, R1 = Ph, R, = E t Gemonil (111) R, = Me, & = R3 = E t
5-ethyl-5-phenylbarbitwic acid
grand ma1
drowsiness, rash
1-methyl-5-ethyl-5 ~benvlbarhituric . . . acid 1 methyl-5,5-diethylbarbituricacid
grand ma1 -
drowsiness, rash
grand ma1
drow%iness,rash, increased irritability
5-ethyl-5-phenylhexahydropyrimidine4,6-dione
grand mal, vertigo, nausea, oceas~on- vomiting, sllv ~ s v - drowsiness chb&oiar
less effective than ( I ) same (11)
...
fairly safe
(4)
LNH C N H I Mysoline (IV)
HYDANTOINS
H
Dilentin (V) R, = H,R, = Rn = Ph Nirvanol (VI) R, = H , % = Ph, R1 = Et Mesantoin (VII) R, = Me, Rs = Ph, Rs = E t Thiantain (VIII) R. = H. R, = Ph., R.- = '2-thienylNuvarone (IX) R, = Me, Rz = Ph, RJ = H Peganone (XI R, = Et. Rz = Ph, RI = H 200
... rash, dizziness, overgrowth of eums. difficultv $focusing ey& 5-ethyl-5-phenylhydantoin grand ma1 rash, fever,, , .. eosinoph~ba 3-methyl-5-ethyl-5-phenylhydantoin grand mal, rash, drowsiness, occasionaplastio anemia, ally psyagranulocytosis, chomotor hepatic injury 5-phenyl-5-(2-thieny1)hydantoin petit ma1 liver damage withdrawn 5,5-'diphenylhydantoin
grand ma1
. ...
3-methyl-5phenylhydantoh.
grand ma1
3-ethyl-5-phenylhydantoin
grand ma1
rash, drowsiness, withdrawn aplitstic anemia, agrrsnulocytosia ? appears to be quite safe
(6)
(eyjx
. . .. ,
(8)
(9)
(10)
...
JOURNAL OF CHEMICAL EDUCATION
will be a good anticonvulsrtnt drug. Table 1 lists those organic compounds which most effectively control seiznres in humans. Compounds (I) through (XX) demonstrate that up to this time only a limited number of chemical structures are of value in controlling seizures. Much work has been done to determine the cause of nerve cell discharges bringing about seizures, and to fathom the mechanism of action of the anticonvulsant drugs (19). So far these riddles have not been solved. However, certain results may point the way to the answer. First let us take a look a t how, theoretically, chemical compounds can prevent seizures. They may act (a) on lesions not connected with nerve cells, (b) on
nerve cells which have been changed due to an outside disease-causing influence, ( e ) on normal nerve cells to prevent their joining in the "chain reaction" of excessive electric discharges (80). STRUCTURAL CORRELATIONS
Several of the compounds used are racemic mixtures, each compound possessing an asymmetric carbon atom. The dextro-form of Nirvanol (VI) is less toxic than the levo- form, hut also less active as an anticonvulsant drug. If racemic Mesantoin (VII) is administered to a patient, primarily levo-Nirvanol is found in the plasma (81). This indicates that somewhere in the metabolism demethylation took place. Butler (88) seems to believe that the N-alkyl group
Usejul in the treatment of
Possible side
Chemical name
Tridione (XI) R, = R, = R8 = Me
3,5,5-trimethyloxazolidine-2,4dione
~ e t ima1 t
may aggravate grand ma1 semures
Pamdione (XII) R, = R, = Me, Rs = E t Dimediane (XIII) R, = Et, RI = Rs = Me Malidone (XIV) R, = allyl, RS = Me, R, = H Epidon (XV) R, = H. R2 = Rs = Ph
petit ma1 3,5-dimethyl-5-ethyloxazolidine2,4dione petit ma1 3-ethyl-5,5-dimethyloxaaolidine2,4dione 8 petit ma1 3-allyl-5-methylaxazolidine-2,4dione
drowsiness, nausea, agranulocvtosis, adastic animia, photophobia sim~larto (XI) similar ta (XII)
less toxic than
similar to (XII)
no photophobia. large dosages
effecta
Comments
Refeyewe
OXAZOLIDINEDIONES
5,5-diphenyloxasolidine-2,4dione
grand ma1
?
Milontin (XVI) R = H
N-methylphenylsuccinimide
petit ma1
Celontin (XVII) R = Me
N-methyl-a-methyl-a-phenylsuccinimide
petit mal, psychomotor
nausea, dizziness, drowsinese. renal damage ?
less toxic than
(XI)
l\----. XTTi
ron,,ir'?d
/
/I
0
...
(13)
does not seem to aggravate grand ma1
(14)
seizures
phenylaeetylurea
psychomotor
2-phenylisohutyrylurea
petit m d
CICH,' Hibicon (
VOLUME 34, NO. 4, APRIL, 1957
re uires carepsychic changes, gastrointestinal handling symptoms, rash, liver damage liver damage withdrawn
YUI
ousness, gastrointestinal distress
(15)
ing a t one time
201
must come off before there can be any anticonvulsant action. However, conflicting evidence may be presented regarding effectiveness of N-alkylation. If the 3-methyl group is removed from Tridione (XI) a compound of lesser activity results. Conversely, 5,5dipropyloxazolidine-2,4dioneshows anticonvulsant activity, hut loses it on methylation of the nitrogen in the &position (11). This is also trne of Dilantin (V). But 5-phenylhydantoin does not show activity until it has been alkylated to substances like Nuvarone (IX) or Peganone (X). Mesantoin (VII) is preferred to Nirvanol (VI) and Mebaral (11) to Phenobarbital (I). If demethylation precedes anticonvulsant activity, compounds without the N-alkyl should be more effective. This does not seem to be true in all cases. Conceivably, factors prior to, or during dealkylation are of importance in determining the action of the drnm It might be suggested that anticonvulsant drugs operate by a mechanism which involves antagonism to some chemical in the body, similar to the sulfonamide drug antagonism to p-aminobenaoic acid. HOTVever, this would not account for the activity of noncyclic compounds like Phenurone (XVIII), (XIX), or Hibicon (XX). At one time it was proposed that anticonvnlsant activity was caused by metabolic products of the drngs. Straight-chain compounds, diphenylhydantoic acid and diphenylaminoacetic acid have been isolated as metabolites of Dilantin (V) and phenylacetic acid and derivatives as metabolites of Phenurone (XVIII). None of the metabolites show anticonvulsant activity (19). Some attention should be paid to the electron distribution of the anticonvnlsant drug molecule, i.e., the "molecular orbital" picture of the molecule as well as its strnctnre. Drug-protein interaction may be due to hydrogen bonding, and/or chargetransfer complex formation. Both Dilantin (V) and Epidon (XV) show grand ma1 seizure antagonism, with Dilantin being the more potent compound. Since the only difference in structure of two chemicals is in the 1-position, it may be deduced that some interaction in this position contributes to anticonvulsant activity, and that this interaction is more pronounced with an N-H group present than with an -0-- atom, be it a local interaction, or a "molecular orbital" effect. Although presence of phenyl groups, generally, is necessary in a to give protection against grand ma1 seiznres, this is not trne when it comes to protection against petit ma1 by oxazolidinedione strnctures. Here the only substituents present are alkyl groups, which, in their electronic behavior, are quite different from aromatic radicals. Only when the -0linkage in the Oxazolidinediones is changed to a -CH2group, as in (XVI), will a phenyl snbstituent in the 5-~ositioncontribute to petit ma1 protection If, on the other hand, this same -CHz-linkage is replaced by an N-H group, without changing the remainder Of the there is Obtained Nuvarone (IX) a grand ma1 antagonist. It may be that rr-electrons from the phenyl ring and p-electrons from the ring may form a resonance 'ystem ('3). This rr-p resonance, however, will be nearly eliminated
-
202
by the insertion of the -CHZ- group in (XVI), thus, conceivably, contributing to petit ma1 activity. A look a t glutarimide derivatives will further indicate the importance of proper location of phenyl groups. The compound
a-methyl-ru-phenylglutarimide, successfully inhibits Metrazole-induced convulsions in test animals. However, p-phenylglutarimide possesses only negligible anticonvulsant activity (34). The phenyl group in the 8-position is isolated from the heterocyclic ring pelectrons by two -CHr groups, thus making xelectron participation practically impossible. Phenurone (XVIII), by being modified to structure XIX, loses its psychomotor potency but acquires petit ma1 activity. The addition of two methyl groups on the ru-carbon removes any available hydrogen on this carbon atom, and also changes the electronic configuration of the molecule sufficiently to give it a different activity spectrum. The above examples are cited to suggest that electron distribution in the drug molecules might be an important point in determining anticonvulsant activity. ,
ACKNOWLEDGMENT
The author takes pleasure in expressing his gratitude to Dr. M. A. Spielman, .Director of Research Evaluation, Ahbott Laboratories, North Chicago, Illinois, for valuable suggestions, and for his patience in discussing this topic. Gratefully ackno~rledged is the help of Professor Charles D. Hurd, Xorthnestern University, regarding the nomenclature of the snccinic and glutaric acid derivatives. LITERATURE CITED ( 1 ) GIBBS,F . A,, AND E. L. GIBBS,"Atlas of Electroencephalography," L. A. Cummings Printing Co., Csmhridge, Mass., 1941. ( 2 ) ( a ) LENNOX,W. G., "Science snd Seizures," Hsrpw and Bras., New York, 1941. ( 6 ) PUTNAM,T. J., "Con-
vulsive Seizures," J. B. Lippincott Co., Philadelphia, .,,A=
1Y-a.
( 3 ) RICHARDS, R. K., el al., "Test Methods," Abhatt Labor* tories, N. Chicago, Ill. (4) BOON,W. R., e l a L to Imperisl Chem. Ind. Ltd, U. S. Patent 2,567,279 (1951). ( 5 ) WARE,E., Chem, Reus,, 46, 403 (1950), ( 6 ) ((1) BLITZ,H . , Ber., 41, 1301 (1908). ( 6 ) BUNNAVANT, W. R., AND F. C. JAMES,J . 4 m . Chew. Soc., 7 8 , 2740 (1956). ( 7 ) MERRITT, H . H., AND T. J. PUTNAM, J . A m . .Wed. A~soc., 111, 1068 (1938). ( 8 ) Chem. Fabrik vorm. Sandoa, Swiss 166,004, Feh. 16, 1934. ( 9 ) SPURLOCK, J. J., U. S. Patent 2,366,221 (1945). (10) I. J., AND W. J. C ~ o s J~. , OTB. Chem., 15, 1020 (1950). (") SPIELMAN, M. A., J. Am. ~ h mSOC., . 66, 1244 (1942). R. W . , J . Am. Chem. Soc., 63, 2376 (1941). ( 1 2 ) STOUGHTON, ( 1 3 ) MILLER,C . A,, AND I . M. LONG,J . Am. Chem. Sot, 7.3, 4895 (1951). ( 1 4 ) LONG, L. M.! private communication. ( 1 5 ) SPIELMAN, M. A,, el al., J . Am. Chem. Soe., 7 0 , 4189 (1948). ( 1 6 ) WILK,I . J., AND M. A. SPIELMAN, U. S. Patent 2,571,639 (1951).
wILK,
JOURNAL OF CHEMICAL EDUCATION-
(21) BUTLER, T . C., J. Pharnt. Ezp. T h e ~ a p . 110, , 120 (1951). (22) BUTLER,T. C., J . Am. Phamt. Assoe., 44, 367 (1955). (23) BRAUDE,E. A , , AND F. C. NACHOD, "Determination of Organic Structures by Ph.vsira1 Methods," Academic Press, Ine., Kew York, 1955, p. 144 ff. (24) MAILWALL, P. G., A N D D. K. VALLANCE, J. Pharot. Phamoeol., 6, 740 (1954).
(17) P R ~B., , Helv. Chim. Ada., 35, 780 (1952). (18) KUSHNER, S., el al., J. 079. Chern., 16, 1287 (1951). J. E. P., AND J. U. TAYLOR,"Epilepsia. Third (19) TOMAN, Series, Val. I," November, 1952, with 164 references. (20) GOODUN, L. S., AND A . GILMAN,"The Pharmacological Basis of Therapeutics," 2nd ed., The Macrnillan Co., New Yark, 1955, p. 179.
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