Ali the studied compaunas exhibiied synergismwith chloral hydrate, and six also with evipan. Synergism wit/z chloral hydrate was so strong that ajter jive oj the ...
ARCHIVUM
IMMUNOLOGIAE
ET THERAPIAE 1970, 18, 270
EXPERJMENTALIS
PHARMACOLOGIC PROPERTJES OF DERIVATIVES 3-PHENYL-3-HYDROXYGLUTARIC ACID
OF
,. .-
by
. MARIAN
WILlMOWSKI,
LIDIA
and Departrnent
KĘ;DZIERSKA,
JÓZEF
of Pharmacology,
PRA
JADWIGA
BARCZVŃSKA
DOTA
Mcdical School, Wrocław
)
The pharmacologic properlies oj 11 tierivatives oj s-tiydroxy-s-otunytpropaner.s-dicarboxytic acid were studied. Three derivalives, S2, S6 and SI1, are sotubie in water and much more toxic than the remaining compounds, which are insoluble in water. Screening tests showed that presence oj the diethylamide group at es of the propane chain causes greater spontaneous molility oj mice. Most oj the compoutuir had 1/0 injluence on arterial blood pressure or respiralion. Ali the studied compaunas exhibiied synergismwith chloral hydrate, and six also with evipan. Synergism wit/z chloral hydrate was so strong that ajter jive oj the preparaiions all the mice died, and ajter fłve others some oj the mice. Two oj the compounds (SI and S2) abolished convulsions induced with strychnine, and nearly all delayed convulsions after pentamethylenetetrazol, witii the exception oj SI1, and S9, whiclt had an opposite effect, Ali the preparations, except S2, increased the number oj mice dropping jrom the rota-rod. The derivatives oj propane-r.s-dicarboxytic acid exhibited pharmacologic activity much stronger than that oj their analogues, derivatives oj propan et.ż-dicarboxytic acid. Preparation S7 merits attention, whicn in spite of markedly increasing spontaneous motility, in the rema in ing tests showed depressive activity without influencing blood pressure or respiration.
In publications of recent years, the problem of the role of y-aminobutyric acid and its metabolite, y-hydroxybutyric acid and internal ester y-butyrolactone is frequently discussed. The problem has been studied in animal experiments 1,2, 4, 6, 8, 15, 17, as well as clinically 5, 11, 12. As a result of the favorable results of these experiments, the sodium salt of y-aminobutyric acid has found use as an adjunctive drug in anesthesiology, mainly in neurosurgery and operations on the respiratory tract, making possible reduction of the doses of anesthetics 12. The hypothesis has been proposed that y-hydroxybutyric acid and its lactone exert an indirect effect on the central nervous system. DANA et al. called attention to the possible influence of the sodium salt of y-hydroxybutyric acid on the metaboli sm of y-aminobutyric acid. According to this hypothesis, presence
PHENYL-HYDROXYGLUTARIC
ACIDS
271
of succinic acid in the central nervous system is connected with the formation of succinic semialdehyde under the influence of y-aminobutyric acid, as wel1 as the sodium salt of y-hydroxybutyric acid. BESSMANand FISHBEIN demonstrated presence of this salt in the brain of rats, and NIRENBERGand JAKOBYfound an enzym e catalyzing its transformation to succinic semialdehyde. e-Ketoglutarle transaminase, which transforms y-aminobutyric acid into succinic semialdehyde, was isolated from the mamillary bodies in the brain already in 1953 by BESSMAN, ROSEN and LAYNE (cit. according to l). The problempf the presence of endogenous y-hydroxybutyric acid and its lactone in the brain of laboratory animals is still under discussion, and the experimental results are contradictory 2,4,6, 17. According to SIEROSŁAWSKA 15, som e of the free amino acids, including y-aminobutyric acid, may be synaptical1y active, Irke the biogenic amines, and y-hydroxybutyric acid could be a transmitter of inhibitory impulses. Al1the authors agree, however, that exogenous y-hydroxybutyric acid, as well as its lactone, have a depressive effect on the central nervous system. BOBRAŃSKIet al. found that 5-allyl-5-~-hydroxypropylbarbituric acid (D1H, Ipronal) is transformed in vivo and in vitro into derivatives of y-butyrolactone, which we re demonstrated in the cerebrospinal fluid, indicating that this compound may be responsible for the sedative action of Ipronal (cited according to "). HANO and SIEROSŁAWSKAfound that e-ethyl-v-phenylbutyrolactone has tranquillizing properties 8. SOWIŃSKAnoted asimilarity between the esters ot tetrahydrofuranono-ż-e-carboxylic acid and psychotropic drugs 16. PELCZARSKA adduced evidence that y-phenyltetrahydrofuranono-2-~and y-carboxylic acids have properties similar to those of ataractics 13. However, the derivatives of butyrolactone have not only tranquillizing properties, but also convulsant action, for instance ~-~-dimethyl-y-butyrolactone, which was studied by BENDA and PERLES, and the group of compounds studied by ENDERS et al. (cit. acc. to 9). In view of the possibility of cyclization of derivatives of y-hydroxyacids in vitro as well as in vivo, leading to variously substituted derivatives of y-butyrolactone, it may be assumed that other appropriately substituted derivatives of this system will have psychetropie properties. Derivatives of 3-hydroxy-3-phenylpropane-l,3-dicarboxylic acid, i. e. su bstituted glutarie acid, possess a tertiary al cohol group "shielded" by large substituents in their molecule, among others by an aromatic radical, so that their chemical structure resembles that of some ataractic and anticonvulsant drugs. Besides the hydroxyl group, two carboxyl groups in positions 1 and 3 are essential elements of the structure of the molecule. This permits synthesis of a large number of derivatives and, depending on the character of the substituents, intramolecular condensation with formation either of the lactone ring, or of a cyclic acidic imide, i. e. groups with "pharmacophoric" properties.
272
M. WILlMOWSKI
ET
AL.
The syntheses of derivatives of 3-hydroxy-3-phenylpropane-I,3-dicarboxyJic acid are a fragment of more extensive studies on compounds with expected central activity at the Department of Pharmacology of the Medical School in Wrocław. In this study, II compounds with OH, OCH3, NH2, N(C2Hs)2' ONH,l or NH-CO-NH2 as substituents (RI and R2) were invcstigated.
R2
Rl
SI
-NH2
S2
-O
S3
-NH.
-OC1-1a
S4
-OCH.
-NH.
S5
-NH.
-N
-OH
1-14
-NH.
/' C.H, T.Hs
S6
C2H5 -N
