416 Journal ofMedicinal Chemistry, 1974, Vol. 17, No. 4
lytical samples of the phthalimidobutyl- and the phthalimidohexylglutathiones were prepared by recrystallization from ethanolwater. The phthalimidooctyl- and phthalimidodecylglutathiones were recrystallized from DMF-water. S-(w-Aminoalky1)glutathiones. Hydrazinolysis of the phthalimido group was effected by the addition of 0.02 mol of 95% hydrazine to 0.01 mol of the phthalimido-substituted compound dissolved in 50 ml of DMF-water (50:50). The resulting solution was allowed to stir for 2 days at room temperature, by which time the solution had become quite turbid. After neutralization with concentrated HI the suspension was chilled, and the phthalhydrazide was removed by high-speed centrifugation. The supernatant portion was concentrated in uacuo to a low volume, and an additional volume of water was added. After chilling, more phthalhydrazide precipitated and was removed by filtration. The filtrate was then concentrated to very low volume, and the final product was crystallized from solution by the addition of ethanol. The hygroscopic solid was removed by filtration, washed with ethanol, and dried in a heated vacuum desiccator in the presence of phosphorus pentoxide. The final products gave a single ninhydrin spot in the solvent system above. Analytical samples were prepared by first dissolving the products in a minimum volume of hot water and then effecting crystallization by the addition of ethanol.
References ( 1 ) R. Vince and W. B. Wadd, Biochem. Biophys. Res. Commun., 35,593 (1969). (2) R. Vince, S. Daluge, and W. B. Wadd, J . Med Chem., 14. 402 (1971). (3) R. Vince and S. Daluge, J. Med. Chem., 14,35 (1971).
Smith, et al. ( 4 ) F. E. Knock, Lancet, 1,824 (1966). (5) M. A. Apple and D. M. Greenberg, Cancer Chemother. Rep., 51,455 (1967). (6) H. Stern, Science, 124,1292 (1956). (7) R. A. Strzinek, G. R. Vela, V. E. Scholes, and S. cJ. Norton, Cancer Res., 30,334 (1970). ( 8 ) R. A. Strzinek, V. E. Scholes, and S. J . Norton, Cancer Res., 32,2359 (1972). (9) R. A. Strzinek and S. J. Norton, Ter. J . Sci., 2 4 , 3 (1972). (10) P. Cuatrecasas,Annu. Reu. Biochern., 40,259 (1971). (11) H. R. V. Arnstein, G. D. Hunter, H . M. Muir, and A . Neuberger,J. Chem. SOC., 1329 (1952). (12) H. B. Donahoe, R. cJ. Seiwald, Sr., M. M. Neumann, and D. E. Heitmeier, J . Med. Chern., 12,906 (1969). (13) W. Dirsherl and F. W. Weingarten, Justus Liebigs Ann. Chem., 574, 131 (1951). (14) W . C . Austin. M. D . Potter, and E. P. Taylor. J . (’hem Soc., 1489 (1958). (15) W. 0. Kermack and N. A . Matheson, Biochem. J . . 65, 48 (1957). (16) J. C. Sheehan and V. S. Frank, J . Amer. Chem. Soc., 71, 1856 (1949). (17) F. E. King and D. A . A. Kidd, J. Chem. Soc., 3315 (1949). (18) M. Dixon and E. C. Webb, “Enzymes,” 2nd ed. Academic Press, New York, N. Y., 1964, p 324. (19) T. Bartfai, K . Ekwall, and B. Mannervik, Biochemistn, 12, 387 (1973). (20) M . Dixon, Biochem. J., 55, 170 (1953). (21) P. Cuatrecasas and C. B. Anfinsen, Methods Enrymoi., 22, 345 (1971). (22) E. Racker, J . Biol. Chem.. 190,685 (1951).
Action of ( S ) -and (R)-Para-SubstitutedAmphetamine Hydrochlorides and (as)-and (aR)-p -Chloronorephedrine and (as)- and (aR)-p -Chloronorpseudoephedrine Hydrochlorides on the Level of 5-Hydroxytryptamine and the Activity of Tryptophan Hydroxylase in Rat Brain??1 Howard E . Smith,* Elizabeth P. Burrows, Jeffrey D. Miano, Department of Chernistr)., Vanderbilt University, Nashville, Tennessee 37235 Charles D. Mount, Department of Chemist?, Tennessee State University, Nashville, Tennessee 37203 Elaine Sanders-Bush, and Fridolin Sulser Department of Pharmacology, Vanderbilt L‘nicersity School of Medicine and Tennessee Neuropsychiatric Institute. .Vashcille, Tennessee 37203. Receiced August 15, 1973 Both (Sj-(+)- and (R)-(-)-p-chloroamphetamine hydrochloride cause a reduction in the level of 5-hydroxytryptamine (serotonin, 5-HT) and the activity of tryptophan hydroxylase in rat brain. The R isomer induces a more rapid decline in 5-HT which is of shorter duration. The effect of this isomer on tryptophan hydroxylase activity disappeared 2 weeks after injection, but the effect of the S isomer persisted. These results indicate that different mechanisms are involved in the short- and long-term effects. ( S ) - ( + ) -and ( R ) - (-)-p-nitroamphetamine hydrochloride both reduce 5-HT levels and tryptophan hydroxylase activity 4 hr after injection, with some recovery after 2 weeks. Since (as)-(-)- and (aR)-(+)-p-chloronorephedrine hydrochloride and (as)-(+)- and (nR)-(-)-p-chloronorpseudoephedrine hydrochloride do not have a significant effect on the level of 5-HT or the activity of tryptophan hydroxylase, /3-hydroxylation is not an important factor in either the short- or long-term effects of p-chloroamphetamine hydrochloride on serotonergic neurons. T h e administration of racemic p-chloroamphetamine hydrochloride [(&)-la]t o rats leads to a marked and longlasting reduction of the levels of 5-hydroxytryptamine (serotonin, 5-HT) and 5-hydroxyindoleacetic acid (5HIAA) and the activity of tryptophan hydroxylase in the tThis is paper XV in the Department of Chemistry, Vanderbilt Universi-
t? series, Optically Active Amines. For paper XIV see ref 1.
$Taken in part from the M . S . Thesis of C . D . M . , Tennessee State University, May 1973.
brain.2 Although some recovery is observed, all three components are still significantly reduced 4 months after a single injection of ( & ) - l aTryptophan . hydroxylase activity in uitro, however, was unaffected by addition of the racemic drug.3 Since it is known t h a t enantiomers of a drug can produce different pharmaco~ogica~effects,4 we have now compared the effect of (SI-(+)- and (R)-(-)-p-chloroamphetamine hydrochlorides36 [(S)-la and @)-la] on the
(S)- and (R)-Para-Substituted Amphetamine Hydrochlorides
H I
ROCH2+H3Ci I
CH3
(S)-la, R = C1 (S)-2a, R = H (S)-3a,R = CH,CO (S)-4a,R = NO, (S)-5a,R = NHJC1
Journal of Medicinal Chemistry, 1974, Vol. 17, No. 4 417
metabolite of (f)-p-chloroamphetamine, we have synthesized the respective hydrochlorides as their racemic modifications15J6 a n d have examined the effects of -)and (aR)-(+)-p-chloronorephedrine hydrochloride [(as)6a and (&)-Gal and (&)-(+)- and (aR)-(-)-p-chloronorpseudoephedrine hydrochloride [(aS)-7a and (aR)-7a], obtained by resolution of the racemates, on the levels of 5-HT and the activity of tryptophan hydroxylase in rat brain.
(as)-(
R'
H
OH
R2 H
R3 CH, (aS)-Ga,R' =C1; R2=OH; R3 = H (aS)-7a, R' = C1; R2 = H; R3 = OH (S)8a, R' = OH; R2 R3= H (aS)Ba, R' = R2 =OH; RJ = H (aS)-lOa,R' = OH; R2,= H; R3= OH (aS)-13a,R'=H; R2=OH; R 3 = H (aS)-14a,R' = R2= H; R3 = OH levels of 5 - H T a n d the activity of tryptophan hydroxylase in rat brain. This seemed especially important in view of the report t h a t only one enantiomer of p-acetyldeoxyephedrine hydrochloride (N-methyl derivative of 3a) was active in lowering levels of 5 - H T in mice brain.7 Not only was (S)-p-acetyldeoxyephedrinehydrochloride ineffective, b u t it blocked t h e effect of its enantiomer when both were administered together.7 In order t o assess the generality of the consequences of a substituent a t the para position of amphetamine, we have also examined the effect of ( S ) - ( + ) -and (I?)-(-)-p-nitroamphetamine hydrochlorides [(S)-4a a n d (R)-4a] a n d (5')-(+ ) - a n d (I?)-( - ) p a m i n o a m p h e t a m i n e dihydrochloride9 [(S)-5a a n d (R)-5a] on 5-HT levels and tryptophan hydroxylase activity in rat brain. T h e finding t h a t ( A)-p-chloroamphetamine hydrochloride [(*)-la] inhibits the activity of tryptophan hydroxylase in vivo b u t not in vitro3 suggests the possibility of the formation of an active metabolite of (*)-la in vivo. The metabolic pattern of ( S ) - (+)-amphetamine [(S)-2b] in ratsl0-l2 a n d the observation t h a t ( & ) - l ais a substrate for dopamine P-hydroxylasec suggest one of the enanthiomers of p-chloronorephedrine (6b) or p-chloronorpseudoephedrine (7b) as a likely candidate for such a metabolite. In rats, (S)-2b is metabolized t o (5')-p-hydroxyamphetamine [(S)-8b], which is subsequently converted by dopamine P-hydroxylase to a metabolite identified as p-hydroxynorephedrine.l2 This metabolite has been implicated in the persistent reduction of brain norepinephrine after the adT h e absolute configministration of (S)-2bt o uration of (S)-8bfollows from the known absolute configuration of its precursor,14 (S)-2b,b u t it has not been established whether the major metabolite of (S)-8b is (aS)-phydroxynorephedrine [(aS)-9b]or (as)-p-hydroxynorpseudoephedrine [(as)-lob]. In order to ascertain the possible role of an enantiomer of p-chloronorephedrine [(aS)-6bor (aR)-6b] or of p-chloronorpseudoephedrine [(aS)-7b or (aR)-7b] as an active $Signs in parentheses refer to rotatory powers observed with sodium D light for the amine hydrochlorides in water and for the amines and Schiff bases in absolute ethanol. It is to be noted that (S)-(+)-amphetaminehydrochloride [(S)-2a] is dextrorotatory in water and levorotatory in absolute ethanol.5 =C.Brown, University of Tennessee School of Medicine, personal communication, 1973.
R2 CH3 (aS)-lla, R' = OH; RL= H (aS)-12a, R' = H; R2=OH (S)-15,R'=R2=H
H
(R)-16
The relative configurations of (*)-6a and (A)-7a were assigned earlier16 by their mode of synthesis and are now confirmed by comparison of their pmr spectra with those [(as)-llb], (as)-pseudoephedrine of (&)-ephedrine 12b], (*)-norephedrine hydrochloride [(A)-13a], and +)-norpseudoephedrine hydrochloride Ida]. The absolute configurations of these models are ( hydrochloride known in t h a t ( a s ) - -)-norephedrine [(aS)-13a]has been related to ( a s ) - -)-ephedrine ( hydro( chloride [(aS)-lla]l7 and ( a s ) - +)-norpseudoephedrine hydrochloride [(aS)-14a]to ( a s ) - +)-pseudoephedrine ( hydrochloride [(aS)-12a].l8 Both ( a s ) - l l a and (aS)-12a have been converted to (S)-( +)-deoxyephedrine hydrochloride [(S)-13],19which has been prepared from ( S ) (+)-amphetamine hydrochloride [(S)-2a].20( a s ) - l l a has also been obtained from (R)-mandelic acid21 [(I?)-161and (aS)-12afrom (S)-16.20 T h e absolute configurations of the optically pure p chloronorephedrine and p-chloronorpseudoephedrine hydrochlorides were established by preparation of the Schiff bases, (aS)-(+)-N-(5-bromosalicylidene)-p-chloronorephedrine [(aS)-6c]a n d (aS)-(+)-N-(5-brornosalicylidene)-pchloronorpseudoephedrine [(aS)-7c], and application of the N-salicylidene sector rule22 t o an interpretation of their respective CD spectra. Examination of the CD spectra of the N-5-bromosalicylidene derivatives (R)-lc, ( S ) 2qZ3(aR)-13c,a n d ( a s ) - l 4 cand the N-salicylidene derivatives (S)-2d23and ( a s ) -14d, prepared from the respective amines, affirms the validity of the sector rule and the utility of N-5-bromosalicylidene derivatives.
[(as)(as)-(
[(as)-
/
R?
R3 CH, (S)-lc,R' = C1; R2 = RJ = H; R? = Br (S)-ZC, Rl = R2 = R3 = H; R4 = Br
(S>2d, R1=R'=R3=R4=H (aS)-Gc,R' = C1; R3=OH; RJ = H; R' = Br (aS)-7c, R' =C1; RL= H; R3 =OH; R' = Br (aS)-13c, R' = H; R2= OH; R3 = H; R' = Br (aS)-Mc,R' = R2= H; R3 = OH; R' = Br (aS)-14d, R' = R2 = H; R3 = OH; RI = H Results and Discussion Synthesis. ( S )-( ) - and ( R )-( - ) p n i t r o a m p h e t a m i n e hydrochlorides [(S)-4aand (R)-4a]were obtained by crys-
+
418 Journal of Medicinal Chemistry, 1974, Vol. 17, No. 4
Table I. P m r D a t a for Ephedrine and Related Compoundsa
(+)-6a (lt)-7a (aS)-llbe ( O S -12be ) ( lt)-13a (4-14a
3.60 3.50 3.54 3.55 3.55 3.50
5.10 4.58 5.62 4.25 5.11 4.65
(3.5) (8 .O) (4 . O ) (8.2) (4.0) (9.0)
1 . 1 2 (7.0) 1 . 1 0 (7 . O ) 1 . 8 2 (6.0) 1 . 7 0 (7.0) 1 . 1 5 (7.0) 1 . 1 2 (7.0)
aHydrochlorides in C D 3 0 D and free bases in CDCl,. bDownfield from TMS. CMultiplet. dDoublet. eData from ref 24. tallization of the hydrochlorides resulting from nitration of (S)-2a and of (R)-2a.8 Catalytic hydrogenation of (S)4a and ( R ) - 4 a gave (S)-5a and respectively. (S)4a was also converted in two steps to (S)-N-phthaloyl-pnitroamphetamine [(S)-18, Scheme I], which was hydrogehydronated to (S)-N-phthaloyl-p-aminoamphetamine chloride [(S)-19]. Diazotization of (S)-19 followed by hy( hydrodrazinolysis yielded ( S ) - +)-p-chloroamphetamine chloride [ @ ) - l a ] . T h e conversion (S)-2a to ( S ) - l a confirms the earlier assignment6 of the S configuration to the dextrorotatory isomer of la. ( R ) - l a was obtained by resolution of (*)-la as its N-acetyl-L-leucinate salt.6 Scheme I I NaOH
(S)-4a 2 phthalic anhydridr
CH
1
0
(*)-p-Chloronorephedrine hydrochloride15J6 [(*)-sa] was synthesized in three steps from 4'-chloropropiophenone (see Experimental Section). Inversion of configuration a t the @-carbon atom by treatment of the N-acetyl derivative of (*)-6a with thionyl chloride followed by aqueous alkali produced ( f ) - 7 a . I 6 (*)-6a was resolved using N-acetyl+ and N-acetyl-D-leucine, while the enantiomers of (*)-7a were supplied to us by Dr. J . Lafferty, Smith Kline & French Laboratories. Configurational Studies. T h e pertinent p m r d a t a for (*)-p-chloronorephedrine hydrochloride [( *)-6a] and (*)-p-chloronorpseudoephedrine hydrochloride [( *)-7a] are compared with those of the model compounds in Table I. As has been discussed in detail in the case of the diastereomeric ephedrines ( a R ) - l l b and ( ~ 1 S ) - 1 2 bthe ,~~
Smith, et al.
erythro configuration produces a coupling constant for the interaction of the a and 0 protons about one-half as great as does the threo configuration. Similar coupling constants are observed for (*)-13a and ( a S ) - l l a , erythro and threo, respectively. Thus, (&)-6aand (*)-7a have these same respective relative configurations. T h e CD data for the Schiff bases are summarized in Table 11. As reported earlier for (S)-(+)-A'-salicylidenamphetamine22 [(S)-2d], strong positive Cotton effects near 255 and 315 n m correlate with the S configuration. T h e CD spectrum of (5')-2c indicates t h a t the same is true for the AV-5-bromosalicylidene derivative. T h e spectrum of (R)-lc as compared to (S)-2c indicates also no significant change due to the p-chloro substituent on the amine moiety. Also, the observed spectra for (aR)-13c, (aS)-llc,and (aS)-14d confirm that the configuration of the contiguous asymmetric center in these norephedrine derivatives has an insignificant effect on the observed Cotton effects near 255 and 315 nm, the sign of these Cotton effects being determined only by the configuration of a-carbon atom. Thus, (-i-p-chloronor- and ( +)-p-chloronorpseudoephedrine hydrochloride are each assigned the aS configuration on the basis of the CD spectra of their respective N5-bromosalicylidene derivatives, Biological Activity. T h e activity of tryptophan hydroxylase and the levels of 5-hydroxytryptamine (5-HT) in brain were determined in animals killed 4 hr or 2 weeks after injection of the 8-phenylethylamine derivatives (Table 111). In agreement with earlier reports,25,26 both optical isomers of p-chloroamphetamine hydrochloride ( l a ) reduce the level of brain 5-HT. The activity of tryptophan hydroxylase is also significantly reduced 4 hr after injection of both isomers. However, the long-term effects of the two isomers are different. ( R ) - l a induces a more rapid decline in brain 5-HT which is of shorter duration. Moreover, the effect of ( R ) -la on tryptophan hydroxylase activity has disappeared 2 weeks later, while the effect of ( S ) - l a persists. These results indicate t h a t the mechanism of the long-term reduction of the level of 5 - H T and the activity of tryptophan hydroxylase after the administration of ( & ) - l amust be different from the mechanism of the early effects. As discussed previously, it seemed possible that the 8hydroxylated metabolite, p-chloronorephedrine, might be responsible for the long-term effects of ( & ) - l aand particularly of ( S ) - l a . An investigation of all four isomers of the @-hydroxylatedcompound [ ( a s ) - G a , (cuR)-6a, ( a S ) - 7 a , and (nR)-7a] showed, however, t h a t they do not decrease the levels of 5 - H T in brain, either a t 4 hr or 2 weeks after a large dose. The activity of tryptophan hydroxylase was also not appreciably changed, except for a slight decrease 2 weeks after injection of (aS)-Ga.Furthermore, the reduction of tryptophan hydroxylase activity by (*)-la is not prevented by pretreatment with disulfiram, which inhibits dopamine $-hydroxylase27 and should block the in cicw formation of a @-hydroxylatedmetabolite. Four hours after the intraperitoneal injection of 10 mg/kg of ( & ) - l a , the activity of tryptophan hydroxylase in brains of rats pretreated with disulfiram (500 mg/kg ip) was reduced by 34 f 470,while that in brains of rats pretreated with saline was reduced by 50 f 370.Therefore, it appears that 0-hydroxylation of either isomer of l a is not critical for either its short- or long-term effects on serotonergic neurons. Both optical isomers of p-nitroamphetamine hydrochloride (4a) induce a depletion of 5 - H T and a decrease in tryptophan hydroxylase activity within 4 hr. Although considerable recovery occurs in both the levels of the amine and the activity of the enzyme, a significant decrease is still evident 2 weeks later. (SI-(+)-p-Aminoam-
(S)- and (R)-Para-Su bstituted Amphetamine Hydrochlorides
Journal of Medicinal Chemistry, 1974, Vol. 17, No. 4 419
Table 11. EA and C D Spectral Data for Schiff Bases in Absolute Ethanola CD [elb
Compd
EA max,
A, nm
(CC)
Longest a n d shortest A, nm ( [ e l b )
Max, A, nm
([elb)
Min, A, nm ( [elb)
415 (-1,500) 326 ( - 14,000)
415 (600) 328 (3,700) 276 (1,700)e 254 (10,O O O ) e , f
380 ( -900) 280 ( -900) 237
255 ( - 43,000) 233 (+2,200) 500 ( f O )
(S)-2C
470
+ 254 ( +35,000)
370 ($1,100) 277 (+1,000)
399 ( +1,700) 314 (+15,000)
363 (+1,000) 276 (+2,400)
411 (+2,200) 327 ( 12,000)
415 (740) 327 (3,600) 276 (1,600)e 254 (10,OOO)e
A, n m d
455
500 ( I t O )
(R)-lc
=
fO,
237
233 (-8,200) 220 (31,000) 460
500 ( f O )
(S)-2d
403 (630) 316 (4,000) 282 (2,100)e 255 (12,000)
233
254 (+38,000) 228 (-2,700)
214 (27,000) (US)&
460
500 ( f O )
370 (+600) 282 (=to)
417 (1,200) 328 (3,500) 277 (2,400)~ 255 ( l O , O O O ) e ~ ~
243 240 ( - 12,000) 500 ( f O )
(lYS)-7c
417 (1,200) 327 (3,500) 280 (2,400)e 253 (12,OOO)e 223 (38,000)
470 417 (+3,000) 328 (+7,800)
378 (+1,200) 275 (+2,000)
256 (+20,000) 233 (+21,000)
243 (+10,000)
417 (-1,300) 327 ( - 10,000)
370 ( - 500) 282 (-300)
226
220 ( - 15,000) 500 ( & O )
(aR)-13c 415 (1,300) 327 (3,400) 276 (2,500)e 252 (lO,OOO)e
455
256 ( - 21,000)
243
230 (+38,000) 222 (31,000) (aS)-14~
460
500 ( f O ) 415 (1,400) 327 (3,500) 277 (2,400) 253 (11,00O)e,c
412 (+2,700) 327 (+5,000) 275 (-1,600) 255 ( +16,000)
367 (+1,000)
400 (+2,400) 315 (+6,200) 272 (-1,800) 253 ( +16,000)
360 (+700)
293 268 239 ($6,800)
235 (+10,000) ( CYS) -14d
450
500 ( & O )
402 (1,100) 316 (3,900) 278 (3,300)e 255 (14,OOO)f
280 268 235 (+3,000)
225 (+ 13,000) ~~
n~
~
~~
0.00177-0.0280g/lOO ml; length 1 cm; temperature 25-28'. bMolecular ellipticity. CMolecular absorptivity. dEach first
entry at a longer wavelength than a maximum indicates the interval from t h e longest wavelength examined for which S t O . eShoulder. 'Spectrum below 225 n m not determined. BSpectrum below 240 n m not determined. phethamine dihydrochloride [( S)-5a] induces an increase rather than a decrease in 5-HT, while (R)-5a had no effeet. Tryptophan hydroxylase activity is not appreciably changed with either (S)-5aor (R)-5a.
Experimental Section Melting points were taken in open capillary tubes and are corrected. Optical rotations at the sodium D line were measured using a visual polarimeter and 1-dm sample tubes. Pmr spectra were determined with a Varian A-60 or JEOL MH-100 spectrometer and chemical shifts (6) are reported in parts per million (ppm) downfield from TMS as internal standard. All compounds gave pmr signals compatible with their assigned structures and relative configurations, but only those signals necessary for differentiating the various compounds are given. Isotropic electronic absorption (EA) spectra were measured with a Cary Model 14 spec-
[el
=
trophotometer with the normal variable slit and circular dichroism (CD) spectra with a Cary Model 60 spectropolarimeter equipped with a CD Model 6001 accessory and programmed for a spectral band width of 1.5 nm. Elemental analyses where indicated were done by Galbraith Laboratories, Inc., Knoxville, Tenn., and, unless noted otherwise, were within &0.30% of the calculated values. (S)-(+)-p-Chloroamphetamine Hydrochloride [@)- la]. To a solution of NaN02 (152 mg, 2.20 mmol) in concentrated (1.6 ml), stirred at 0", was added glacial HOAc (5 ml) followed by (S)-19(632 mg, 2.00 mmol) in portions. The mixture was stirred 30 min at 0" and then was added slowly to a freshly prepared solution of CuCl (5.0 mmol), prepared from CuS04.5HzO (5.0 mmol) and NaCl (5.6 mmol) by the bisulfite procedure,28 in concentrated HC1 (4 ml) at 0". The mixture was allowed to warm to room temperature and, after stirring overnight, was heated 20 min on the steam bath. It was cooled, diluted with HzO (20 ml),
420 JournalofMedicinal Chemistry, 1974, Vol. 17, No. 4
Smith, et al.
Table 111. Effects of Various 0-Phenylethylamine Hydrochlorides on the Level of 5-Hydroxytryptamine (5-HT) a n d the Activity of Tryptophan Hydroxylase (TH) in Rat Brain" Compd
D ~ m g 1kgh
(S)-la (R)-la
5
(Sj-4a
15 15 15 15 10 10
(R)-4a (S-5a (R)-5a (aS)-6a (c~R)-6a (aS)-7a (&)-7a
5
10
injection ~ % control ~- _ , i S.E.M.r-4 h r__-after . _ 5-HT TH 63 9 i 3 6" 3 4 9 1 1 6 ' 41 5 i 0 g d 16 4 i 1 2 j 170 6 i 9 5" 100 9 i 5 6'92 8 f 3 Be 110 7 i- 2 l e 106 1 i 3 7? 91 8 f 5
55 62 54 51 87 89 88 96 106 86
_____ 1 k 3 4" 7 1 2 0' 6 & 1 gd 7 1 3 0' 0 zz 0 9c
4 rk 4 o c 1 16 3 7 i 7 1' 2 i 3 72 i 3 6?
% control i S.E.M.r 2 weeks after injection - -
5-HT
89 100 94 93
TH
___-
~~
46 6 f 4 61 6 i- 1 81 3 19 68 1 2 7
64 92 71 76
1' 6' 5' 81
6 i- 4 le 1 13 7e 6 i- 2 5
