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A selective inhibitor of serotonin uptake: Lilly 110140, 3-(p-Trifluoromethylphenoxy)-n-methyl-3-phenylpropylamine
Lifs Sci~acas Vol . 15, pp " 471-479 Printed in the II .S .A .
Pergamon Press
A SELECTIVE INHIBITOR OF SEROTONIN UPTAKE : LILLY 110140, 3-(p-TRIFLUOROMETHYLPHENOXY)-N-METHYL-3-PHENYLPROPYLAMINE David T. Wong, Jonq S . Hornq, Frank P . Bymaster, Kenneth L . Hauser and Hryan B . Molloy The Lilly Research Laboratories, Eli Lilly and Company Indianapolis, Indiana 46206 (Received in final fozm 24 June 1974)
SUMMARY Lilly 110140 is a highly selective inhibitor of serotonin uptake into synaptoeomes of rat brain, unlike previous monoamine uptake inhibitors that also inhibit the uptake of norepinephrine and dopamine . Lilly 110140 should be useful in studying the function of serotoninergic neurons and may be helpful in clarifying the role of serotonin in certain types of mental depression . The pinched-off nerve-endings (synaptosomes) of rat brain accumulate putative neurotransmitter substances such as norepinephrine (NE), dopamine (DA), and serotonin (SHT) .
The processes
of accumulation follow saturable kinetics with Rm values specific for each substrate, for example, 6 x 10 - 7M for NE, 2 x 10-7M for DA and 1 x 10 -~M for 5HT (1,2,3) .
The uptake process of each
amine has a different sensitivity toward various drugs .
The
uptake of 5HT is profoundly inhibited by the tertiary amine containing tricyclic agents, chlorimipramine and imipramine, while the uptake processes in the catecholaminergic neurons are more sensitive to the secondary amine containing compounds, desipramine and nortriptyline (4,5) .
We also reported earlier that the 5HT
specific ~iptake was more sensitive to the inhibition of 4-chloroamphetamine than amphetamine (3) . These findings have led us to search for other ca~pounde that may differentiate the uptake sites of monoamines . 471
in the
Vol . 15, No . 3
A Selective Inhibitor of 5AT IIptake
47 2
present communication, we shall report the discovery of a new compound, Lilly 110140 (Fig . 1), which shows in vitro and in vivo selectivity in inhibition of 5HT uptake into synaptosomes of rat brain . CF3ÎH2 N H
CH3
FIG . 1 The Structure of Lilly 110140, 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine METHODS AND MATERIAL Crude synaptosomel preparations were prepared from a 108 homogenate of whole rat brain in 0 .32M Sucrose .
The measurement
of the uptake of monoamines into synaptosomes was modified from the previously described method (3) .
In a final Volume of 1 ml,
synaptosomes of 1 mg protein were incubated for 3 min at 37oC in Rrebs bicarbonate buffer containing either 5HT (0 .05-2 x 10 - 6M), NE (0 .31-1 x 10 -6M) or DA (0 .1-0 .5 x 10 - 6M) . then chilled in ice and centrifuged .
The samples were
The pellet was rinsed with
the ice-chilled buffer and transferred to counting Vials containing scintillation fluid.
The radioactivity was measured by the
Packard liquid scintillation spectrometer (3) . The effect of drugs on the uptake of 14C-NE by the heart was estimated according to the method developed by Hertting et al (6) . Rats were treated twice with 110140, chlorimipramine or desipramine at 0 and 23rd hr .
14 C-NE of 5 u c/kg (50 mCi/mmole,
Dol . 15, No . 3
47 3
A Selective Inhibitor of 5HT Uptake
New England Nuclear) was intravenously injected 30 min after the last injection of each drug and the animals were decapitated 30 min after the administration of 14 C-NE . RESULTS AND DISCUSSION The kinetic data, either analyzed according to the Lineweaver-Buck method (7) or by the Dixon method
(8), show com-
petitive type of inhibition on uptake of monoamines by 110140 and three tricyclic compounds, chlorimipramine, imipramine, and nortriptyline .
Table 1 shows the inhibition constants (Ri) of
Table 1: Inhibitor constant (Ri) for Lilly 110140 and tricyclic antidepressive agents in inhibition of serotonin, norepinephrine and dopamine uptake into synaptosomea of rat brain. 5HT
NE Ki (M)
DA
5 .2 x 10_ 8
1 x 10_ 5
1 .5 x 10_ 5
Chlorimipramine
4 x 10_8
1 .3 x 10_ 5
6 .2 x 10 -6
Imipramine
2 x 10 -7
2 .4 x 10 -5
1 .8 x 10'S
3 .6 x 10_ 6
8 .2 x 10 -7
3 .1 x 10'6
Lilly 110140
Nortriptyline
Ri values were calculated according to the Lineweaver-Burk method (7) . Ri values for Lilly 110140 were obtained from the Dixon plots (8) . Synaptosomea of 1 mg protein/ml was incubated at 37oC for 3 min in Rreba bicarbonate buffer containing one of the monoamines, 0 .05-2 x 10 -6M 14C-5HT, 0 .3-1 x 10 - 6M 3H-NE, or 0 .10-0 .5 x 10 -6M 3H-DA (2_14C_SHT, 25 mCi/mmole; 7-3H (N)-NE, 15Ci/mmole and 3H(G)DA, lOCi/mmole were obtained from New England Nuclear) . The medium may also include one of the inhibitors : 0 .5-2 x 10 -7M, 110140 ; 10 - 7M, chlorimipramine ; 5 x 10 -7M, imipramine and 1 x 10 -6M, nortriptyline . 110140 and the three tricyclic compounds .
Compound 110140 was a
potent inhibitor of 5HT uptake into synaptosomes with a Ri value of 5 .2 x 10 -8M.
The inhibitory effects on the uptake of NE and
DA were much less, with 200 and 300-fold greater Ri values .
474
A Selective Inhibitor of 5HT Uptake
Vol . 15, No . 3
Therefore, 110140, a secondary amine, has greater affinity for the uptake sites of 5HT than for the sites of NE and DA uptake . The tricyclic compound, chlorimipramine, was not as selective as 110140 in inhibiting the uptake of the three monoamines . Although chlorimipramine was about as active as 110140 in inhibi tion of 5HT and NE uptake with comparable Ri values, it was about 3 times more effective than 110140 in inhibition of DA uptake . The other tertiary amine containing tricyclic antidepressive drug, imipramine, on the other hand, was 4 times less effective than 110140 in inhibition of 5HT uptake .
The secondary amine contain-
ing tricyclic drug, nortriptyline, was more effective in inhibiting the uptake of NE than the uptake of 5HT and DA .
Among the
four compounds, 110140 is the most selective competitive inhibitor of 5HT uptake in nerve-endings of rat brain . Rats were treated with 110140 or chlorimipramine at equimolar concentrations (28 .5 umole/kg i .p .) .
One hr later, their brains
were removed for the isolation of synaptosomes .
Synaptosomal pre
parations from each brain were tested for inhibitors activity on the uptake of 5HT, NE and DA .
Compound 110140 effectively caused
a 56$ inhibition of the uptake of 5HT into synaptosomes from the treated rats while chlorimipramine was less than half as effective (Table 2) .
The uptake activity of NE was slightly enhanced while
the activity of DA uptake was not altered in either group of rata . . The inhibitory effect of 110140 on 5HT uptake persisted for 24 hra Thus, the drug has a high affinity for the central 5HT neurons in whole animals .
The precise aubcellular localization of 110140,
however, is presently unknown .
A recent study on imipramine dis-
tribution showed a greater accumulation of the tricyclic drug in the synaptosomal fraction of a brain homogenate (9) .
It is
Vol. 15, No . 3
47 5
A &elective Inhibitor of SHf IIptake
expected, therefore, that 110140, having such a high affinity for the the 5HT sites, probably localizes in the nerve terminals of 5HT neurone of rat brain. Table 2 : The uptake of monoamines into synaptosomes of control and drug-treated rate . 5HT
NE p mole/mg protein/3 min
DA
Control
9 .691 .35
15 .7210 .32
19 .7411.09
Lilly 110140
4 .2110 .27**
17 .7510 .34**
22 .1211.79
Chlorimipramine
7 .4110 .78*
18 .441 .51**
18 .3310 .39
*p<0 .02 **p<0 .001 Groups of 5 male rate (150 g) were treated with either 28 .5 umole/kg of Lilly 110140 or chlorimipramine. Synaptosames of each brain were prepared from these animals and 10 control animals . The uptake of monoamines were measured at 10 -7M 14C-SHT, 5 x 10 -7M 3H-NE or 2 x 10 -7M 3H-DA .' Other conditions have been described in the text . $arlier work has indicated that inhibition of the uptake process by various agents is generally more pronounced in peripheral than in central NE neurons (10) .
~Pe, therefore, compared the
effect of 110140, chlorimipramine and desipramine on the in vivo accumulation of 14C-NS into rat hearts .
After the injections of
110140 at 28 .5 umole at 0 and 23rd hr, the accumulation of 14 C-NE and its metabolites in the hearts was not significantly affected (Fig . 2) .
However, the administration of the tricyclic agents,
chlorimipramine and desipramine, in equal amounts reduced the uptake activity by 506 and 838, respectively .
Subsequent experi-
ments showed that chlorimipramine at 57 umole/kg was as effective as desipramiae whereas Lilly 110140 remained ineffective in altering Nß uptake into rat hearts .
Thus, these experiments
A Selective inhibitor of 5AT Uptake
47 6
Vol . 15, No . 3
further illustrated the selectivity of 110140 which preferentially inhibited 5HT uptake but not the central or peripheral uptake of catecholamines .
FIG . 2 Effect of Lilly 110140, chlorimipramine and desipramine on uptake of NE into rat hearts . Male rats weighing 100-120 q were twice treated with 110140, chlorimipramine or desipramine at 28 .5 umole mg/kq i .p . within 24 hrs . 14C-NE at 5 uc/kg was intravenously injected 30 min after the last injection of each drug . Hearts were removed 30 min after the administration of 14C-NE and digested in 308 H202 at 60oC . Radioactivity of the digested hearts was monitored by liquid scintillation technique . Other studies in these laboratories also demonstrated the in vivo effectiveness of 110140 inhibition of 5HT reuptake in rat brain.
It reduced 5HT turnover and consequently decreased the
Vol. 15, No . 3
71 Selective
Inhibitor
of 5HT
Dptake
47 7
concentration of 5HIAA in brain without inhibiting monoamine oxidase, potentiated some central effects of exogenous 5HTP, and blocked the depletion of 5HT by 4-chloroamphetamine that required the membrane pump for entry into the 5HT neuron .
The results of
these in vivo studies will be reported in detail elsewhere (11) . We believe that the discovery of specific inhibitors of 5HT reuptake like 110140 will help in elucidating the function of 5HT in brain and the importance of reuptake as an inactivating mecha nism in 5HT neurotransmission (1) .
In addition, such an agent
may find clinical use as a therapeutic agent . Several lines of evidence point to a role of brain 5HT in mental illness, especially in mental depression (12,13) .
Reduced
levels of 5-hydroxyindoles in brain and cerebrospinal fluid of patients with depressive illness and favorable clinical response to treatment with SHTP or tryptophan, precursors that elevate 5HT formation, are two forms of such evidence .
In addition, the
depressive effect of reserpine, which lowers brain 5HT, and the antidepressive actions of monoamine oxidase inhibitors, which elevate brain 5HT, represents pharmacologic evidence for a connection between brain 5HT and mental depression .
The lack of specif-
icity of reserpine and of the monoamine oxidase inhibitors
(they
affect other monoamines like NE and DA as well) makes the interpretation of the findings difficult .
The same lack of specificity
holds for the currently used tricyclic antidepressant drugs, all of which inhibit 5HT reuptake but also inhibit the reuptake of NE and DA to varying degrees .
Thus, the ability of these latter
drugs to improve symptoms of depressive illness may relate to their blockade of 5HT reuptake and subsequent enhancement of
58T
action on receptors, but may equally well result from an action on NE or DA reuptake .
Recently Aaberg et 'al (14) have suggested
A Selective Inhibitor of 5ST Uptake
478
Vol. 15, No . 3
that a subgroup of patients with endogenous depression are deficient in serotoninergic function and would be helped more by a drug that acts selectively on 5HT than by currently available drugs .
Compound 110140 seems to be such a selective agent .
In
addition, 110140 may be an important tool to study the involvement of 5HT in sleep (15), in sexual behavior (16), in the regulation of hypophyseal function (17), and in other possible physiological functions of the central nervous system . REFERENCES 1.
L . L . Iversen, in Biochemistry of Simple Neuronal Models , E . Costa and E . Giacov n~ Eds .TRaven, New Yor , 1~, p . 109 .
2.
S . H . Snyder and J . T . Coyle, J . Pharmacol . Exp . Ther . 165, 78 (1969) .
3.
D . T . Wong, J . S . Horng and R. W . Fuller, Biochem. Pharmacol . 22, 311 (1973) .
4.
A . Carlsson, K . Fuxe and U . Ungerstedt, J . Pharm. Pharmacol. 20, 150 (1968) .
5.
A . Carlsson, K . Fuxe, B . Hamberger and M . Lindquist, Acta Phys io1 . Sçand. 67, 481 (1966) .
6.
G . Hertting, J . Axelrod and L . G . Whitby, J . Pharmacol . Exp . Ther . 134, 146 (1961) .
7.
H. Lineweaver and D . Burk, J. Am . Chem . Soc . 56, 658 (1934) .
8.
M . Dixon, Biochem. J . 55, 170 (1953) .
9.
C . G . Caratach and P . G . Waser, Neuropharmacol . 12, 563 (1973) .
10 .
A Carlsson, H . Corrodi, R. Fuxe and T. Hokfelt, Europ . J . Pharmacol . 5, 367 (1969) .
11 .
R . W . Fuller and K. W . Ferry, Fed . Froc . 33, 255 (1974) .
12 .
H. Weil-Malherbe and S . I . Szara, The Biochemist tional and e erimental Ps chores T omas, pr ng 2 no s, ~ p.
13 .
J . J . Schildkraut, Ann . Rev . Pharmacol . 13, 427 (1973) .
14 .
M. Aaberg, L . Hertilsaon, D . Tuck, B. CronhoLa and F . Sjogviat, Clin . Pharmacol . and Therap . 14, 277 (1973) .
of Funce ,
Vol. 15, No . 3
A Selective Inhibitor of 5HT Dptaka
479
15 .
M. Jouvet, Science 163, 32 (1969) .
16 .
B . J . Meyerson, Acta Physiol . Scand. 63, suppl. 241 (1966) .
17 .
R . Rordon, F . Javoy, G . Vassent and J . Glowinski, Europ . J . Pharmacol . 4, 1969 (1968) .
Pergamon Press
A SELECTIVE INHIBITOR OF SEROTONIN UPTAKE : LILLY 110140, 3-(p-TRIFLUOROMETHYLPHENOXY)-N-METHYL-3-PHENYLPROPYLAMINE David T. Wong, Jonq S . Hornq, Frank P . Bymaster, Kenneth L . Hauser and Hryan B . Molloy The Lilly Research Laboratories, Eli Lilly and Company Indianapolis, Indiana 46206 (Received in final fozm 24 June 1974)
SUMMARY Lilly 110140 is a highly selective inhibitor of serotonin uptake into synaptoeomes of rat brain, unlike previous monoamine uptake inhibitors that also inhibit the uptake of norepinephrine and dopamine . Lilly 110140 should be useful in studying the function of serotoninergic neurons and may be helpful in clarifying the role of serotonin in certain types of mental depression . The pinched-off nerve-endings (synaptosomes) of rat brain accumulate putative neurotransmitter substances such as norepinephrine (NE), dopamine (DA), and serotonin (SHT) .
The processes
of accumulation follow saturable kinetics with Rm values specific for each substrate, for example, 6 x 10 - 7M for NE, 2 x 10-7M for DA and 1 x 10 -~M for 5HT (1,2,3) .
The uptake process of each
amine has a different sensitivity toward various drugs .
The
uptake of 5HT is profoundly inhibited by the tertiary amine containing tricyclic agents, chlorimipramine and imipramine, while the uptake processes in the catecholaminergic neurons are more sensitive to the secondary amine containing compounds, desipramine and nortriptyline (4,5) .
We also reported earlier that the 5HT
specific ~iptake was more sensitive to the inhibition of 4-chloroamphetamine than amphetamine (3) . These findings have led us to search for other ca~pounde that may differentiate the uptake sites of monoamines . 471
in the
Vol . 15, No . 3
A Selective Inhibitor of 5AT IIptake
47 2
present communication, we shall report the discovery of a new compound, Lilly 110140 (Fig . 1), which shows in vitro and in vivo selectivity in inhibition of 5HT uptake into synaptosomes of rat brain . CF3ÎH2 N H
CH3
FIG . 1 The Structure of Lilly 110140, 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine METHODS AND MATERIAL Crude synaptosomel preparations were prepared from a 108 homogenate of whole rat brain in 0 .32M Sucrose .
The measurement
of the uptake of monoamines into synaptosomes was modified from the previously described method (3) .
In a final Volume of 1 ml,
synaptosomes of 1 mg protein were incubated for 3 min at 37oC in Rrebs bicarbonate buffer containing either 5HT (0 .05-2 x 10 - 6M), NE (0 .31-1 x 10 -6M) or DA (0 .1-0 .5 x 10 - 6M) . then chilled in ice and centrifuged .
The samples were
The pellet was rinsed with
the ice-chilled buffer and transferred to counting Vials containing scintillation fluid.
The radioactivity was measured by the
Packard liquid scintillation spectrometer (3) . The effect of drugs on the uptake of 14C-NE by the heart was estimated according to the method developed by Hertting et al (6) . Rats were treated twice with 110140, chlorimipramine or desipramine at 0 and 23rd hr .
14 C-NE of 5 u c/kg (50 mCi/mmole,
Dol . 15, No . 3
47 3
A Selective Inhibitor of 5HT Uptake
New England Nuclear) was intravenously injected 30 min after the last injection of each drug and the animals were decapitated 30 min after the administration of 14 C-NE . RESULTS AND DISCUSSION The kinetic data, either analyzed according to the Lineweaver-Buck method (7) or by the Dixon method
(8), show com-
petitive type of inhibition on uptake of monoamines by 110140 and three tricyclic compounds, chlorimipramine, imipramine, and nortriptyline .
Table 1 shows the inhibition constants (Ri) of
Table 1: Inhibitor constant (Ri) for Lilly 110140 and tricyclic antidepressive agents in inhibition of serotonin, norepinephrine and dopamine uptake into synaptosomea of rat brain. 5HT
NE Ki (M)
DA
5 .2 x 10_ 8
1 x 10_ 5
1 .5 x 10_ 5
Chlorimipramine
4 x 10_8
1 .3 x 10_ 5
6 .2 x 10 -6
Imipramine
2 x 10 -7
2 .4 x 10 -5
1 .8 x 10'S
3 .6 x 10_ 6
8 .2 x 10 -7
3 .1 x 10'6
Lilly 110140
Nortriptyline
Ri values were calculated according to the Lineweaver-Burk method (7) . Ri values for Lilly 110140 were obtained from the Dixon plots (8) . Synaptosomea of 1 mg protein/ml was incubated at 37oC for 3 min in Rreba bicarbonate buffer containing one of the monoamines, 0 .05-2 x 10 -6M 14C-5HT, 0 .3-1 x 10 - 6M 3H-NE, or 0 .10-0 .5 x 10 -6M 3H-DA (2_14C_SHT, 25 mCi/mmole; 7-3H (N)-NE, 15Ci/mmole and 3H(G)DA, lOCi/mmole were obtained from New England Nuclear) . The medium may also include one of the inhibitors : 0 .5-2 x 10 -7M, 110140 ; 10 - 7M, chlorimipramine ; 5 x 10 -7M, imipramine and 1 x 10 -6M, nortriptyline . 110140 and the three tricyclic compounds .
Compound 110140 was a
potent inhibitor of 5HT uptake into synaptosomes with a Ri value of 5 .2 x 10 -8M.
The inhibitory effects on the uptake of NE and
DA were much less, with 200 and 300-fold greater Ri values .
474
A Selective Inhibitor of 5HT Uptake
Vol . 15, No . 3
Therefore, 110140, a secondary amine, has greater affinity for the uptake sites of 5HT than for the sites of NE and DA uptake . The tricyclic compound, chlorimipramine, was not as selective as 110140 in inhibiting the uptake of the three monoamines . Although chlorimipramine was about as active as 110140 in inhibi tion of 5HT and NE uptake with comparable Ri values, it was about 3 times more effective than 110140 in inhibition of DA uptake . The other tertiary amine containing tricyclic antidepressive drug, imipramine, on the other hand, was 4 times less effective than 110140 in inhibition of 5HT uptake .
The secondary amine contain-
ing tricyclic drug, nortriptyline, was more effective in inhibiting the uptake of NE than the uptake of 5HT and DA .
Among the
four compounds, 110140 is the most selective competitive inhibitor of 5HT uptake in nerve-endings of rat brain . Rats were treated with 110140 or chlorimipramine at equimolar concentrations (28 .5 umole/kg i .p .) .
One hr later, their brains
were removed for the isolation of synaptosomes .
Synaptosomal pre
parations from each brain were tested for inhibitors activity on the uptake of 5HT, NE and DA .
Compound 110140 effectively caused
a 56$ inhibition of the uptake of 5HT into synaptosomes from the treated rats while chlorimipramine was less than half as effective (Table 2) .
The uptake activity of NE was slightly enhanced while
the activity of DA uptake was not altered in either group of rata . . The inhibitory effect of 110140 on 5HT uptake persisted for 24 hra Thus, the drug has a high affinity for the central 5HT neurons in whole animals .
The precise aubcellular localization of 110140,
however, is presently unknown .
A recent study on imipramine dis-
tribution showed a greater accumulation of the tricyclic drug in the synaptosomal fraction of a brain homogenate (9) .
It is
Vol. 15, No . 3
47 5
A &elective Inhibitor of SHf IIptake
expected, therefore, that 110140, having such a high affinity for the the 5HT sites, probably localizes in the nerve terminals of 5HT neurone of rat brain. Table 2 : The uptake of monoamines into synaptosomes of control and drug-treated rate . 5HT
NE p mole/mg protein/3 min
DA
Control
9 .691 .35
15 .7210 .32
19 .7411.09
Lilly 110140
4 .2110 .27**
17 .7510 .34**
22 .1211.79
Chlorimipramine
7 .4110 .78*
18 .441 .51**
18 .3310 .39
*p<0 .02 **p<0 .001 Groups of 5 male rate (150 g) were treated with either 28 .5 umole/kg of Lilly 110140 or chlorimipramine. Synaptosames of each brain were prepared from these animals and 10 control animals . The uptake of monoamines were measured at 10 -7M 14C-SHT, 5 x 10 -7M 3H-NE or 2 x 10 -7M 3H-DA .' Other conditions have been described in the text . $arlier work has indicated that inhibition of the uptake process by various agents is generally more pronounced in peripheral than in central NE neurons (10) .
~Pe, therefore, compared the
effect of 110140, chlorimipramine and desipramine on the in vivo accumulation of 14C-NS into rat hearts .
After the injections of
110140 at 28 .5 umole at 0 and 23rd hr, the accumulation of 14 C-NE and its metabolites in the hearts was not significantly affected (Fig . 2) .
However, the administration of the tricyclic agents,
chlorimipramine and desipramine, in equal amounts reduced the uptake activity by 506 and 838, respectively .
Subsequent experi-
ments showed that chlorimipramine at 57 umole/kg was as effective as desipramiae whereas Lilly 110140 remained ineffective in altering Nß uptake into rat hearts .
Thus, these experiments
A Selective inhibitor of 5AT Uptake
47 6
Vol . 15, No . 3
further illustrated the selectivity of 110140 which preferentially inhibited 5HT uptake but not the central or peripheral uptake of catecholamines .
FIG . 2 Effect of Lilly 110140, chlorimipramine and desipramine on uptake of NE into rat hearts . Male rats weighing 100-120 q were twice treated with 110140, chlorimipramine or desipramine at 28 .5 umole mg/kq i .p . within 24 hrs . 14C-NE at 5 uc/kg was intravenously injected 30 min after the last injection of each drug . Hearts were removed 30 min after the administration of 14C-NE and digested in 308 H202 at 60oC . Radioactivity of the digested hearts was monitored by liquid scintillation technique . Other studies in these laboratories also demonstrated the in vivo effectiveness of 110140 inhibition of 5HT reuptake in rat brain.
It reduced 5HT turnover and consequently decreased the
Vol. 15, No . 3
71 Selective
Inhibitor
of 5HT
Dptake
47 7
concentration of 5HIAA in brain without inhibiting monoamine oxidase, potentiated some central effects of exogenous 5HTP, and blocked the depletion of 5HT by 4-chloroamphetamine that required the membrane pump for entry into the 5HT neuron .
The results of
these in vivo studies will be reported in detail elsewhere (11) . We believe that the discovery of specific inhibitors of 5HT reuptake like 110140 will help in elucidating the function of 5HT in brain and the importance of reuptake as an inactivating mecha nism in 5HT neurotransmission (1) .
In addition, such an agent
may find clinical use as a therapeutic agent . Several lines of evidence point to a role of brain 5HT in mental illness, especially in mental depression (12,13) .
Reduced
levels of 5-hydroxyindoles in brain and cerebrospinal fluid of patients with depressive illness and favorable clinical response to treatment with SHTP or tryptophan, precursors that elevate 5HT formation, are two forms of such evidence .
In addition, the
depressive effect of reserpine, which lowers brain 5HT, and the antidepressive actions of monoamine oxidase inhibitors, which elevate brain 5HT, represents pharmacologic evidence for a connection between brain 5HT and mental depression .
The lack of specif-
icity of reserpine and of the monoamine oxidase inhibitors
(they
affect other monoamines like NE and DA as well) makes the interpretation of the findings difficult .
The same lack of specificity
holds for the currently used tricyclic antidepressant drugs, all of which inhibit 5HT reuptake but also inhibit the reuptake of NE and DA to varying degrees .
Thus, the ability of these latter
drugs to improve symptoms of depressive illness may relate to their blockade of 5HT reuptake and subsequent enhancement of
58T
action on receptors, but may equally well result from an action on NE or DA reuptake .
Recently Aaberg et 'al (14) have suggested
A Selective Inhibitor of 5ST Uptake
478
Vol. 15, No . 3
that a subgroup of patients with endogenous depression are deficient in serotoninergic function and would be helped more by a drug that acts selectively on 5HT than by currently available drugs .
Compound 110140 seems to be such a selective agent .
In
addition, 110140 may be an important tool to study the involvement of 5HT in sleep (15), in sexual behavior (16), in the regulation of hypophyseal function (17), and in other possible physiological functions of the central nervous system . REFERENCES 1.
L . L . Iversen, in Biochemistry of Simple Neuronal Models , E . Costa and E . Giacov n~ Eds .TRaven, New Yor , 1~, p . 109 .
2.
S . H . Snyder and J . T . Coyle, J . Pharmacol . Exp . Ther . 165, 78 (1969) .
3.
D . T . Wong, J . S . Horng and R. W . Fuller, Biochem. Pharmacol . 22, 311 (1973) .
4.
A . Carlsson, K . Fuxe and U . Ungerstedt, J . Pharm. Pharmacol. 20, 150 (1968) .
5.
A . Carlsson, K . Fuxe, B . Hamberger and M . Lindquist, Acta Phys io1 . Sçand. 67, 481 (1966) .
6.
G . Hertting, J . Axelrod and L . G . Whitby, J . Pharmacol . Exp . Ther . 134, 146 (1961) .
7.
H. Lineweaver and D . Burk, J. Am . Chem . Soc . 56, 658 (1934) .
8.
M . Dixon, Biochem. J . 55, 170 (1953) .
9.
C . G . Caratach and P . G . Waser, Neuropharmacol . 12, 563 (1973) .
10 .
A Carlsson, H . Corrodi, R. Fuxe and T. Hokfelt, Europ . J . Pharmacol . 5, 367 (1969) .
11 .
R . W . Fuller and K. W . Ferry, Fed . Froc . 33, 255 (1974) .
12 .
H. Weil-Malherbe and S . I . Szara, The Biochemist tional and e erimental Ps chores T omas, pr ng 2 no s, ~ p.
13 .
J . J . Schildkraut, Ann . Rev . Pharmacol . 13, 427 (1973) .
14 .
M. Aaberg, L . Hertilsaon, D . Tuck, B. CronhoLa and F . Sjogviat, Clin . Pharmacol . and Therap . 14, 277 (1973) .
of Funce ,
Vol. 15, No . 3
A Selective Inhibitor of 5HT Dptaka
479
15 .
M. Jouvet, Science 163, 32 (1969) .
16 .
B . J . Meyerson, Acta Physiol . Scand. 63, suppl. 241 (1966) .
17 .
R . Rordon, F . Javoy, G . Vassent and J . Glowinski, Europ . J . Pharmacol . 4, 1969 (1968) .