Substituted phenethylamines and anorexia

Prog. Nemo-Paychophamnacol. Pergamon Press Ltd, 1980.

Vol. Printed

4,

SUBSTITUTED Jacques

pp. 341-.340. Great Britain.

in

-s

AND ANOREXIA

DUHAULT, Laszlo Institut

BEREGI

and

Francois

ROMAN

de Recherches Servier Suresnes, France

(Final

form,

July

1980)

Abstract 1. A considerable number of modifications to the phenethylamine useful pharmacological tools for studying regulation of food studies show that anorectic drugs constitute a heterogeneous in animals by different mechanisms.

structure have provided intake. The results of these group, reducing food intake

2. A review of evidence illustrates that pharmacologically induced changes in the activity of monoamine systems are associated with pronounced reduction in food intake. While catecholamines may be involved in the anorectic activity of stimulating agents such asamphetamina the integrity of the serotoninergic system appears to be important for the reduction of food intake induced by the fenfluramine group. 3. The anorectic effect of mazindol seems to depend on both the noradrenergic systems. However, biochemical information suggests an interaction between and the nigroneostriatal DA pathways.

and dopaminergic the central 5-HT

4. Structural modifications in the lateral chain need CF group for anorectic activity, while phenoxy substituted amphetamines have no effect on foad intake, in spite of mild stimulant properties. Kev words

:

anorectic

drugs,

brain

monoamines,

brain

Abbreviations : 5,6DHT : 5,6-dihydroxytryptamine; 5-HT: 5-hydroxytryptamine; 5HTP: 5-hydoxytryptophan; amphetamine.

synaptoscmes,

serotonin

: 5-hydroxy-indola intraperitoneal;

5-HIAA IP:

neurotoxins.

acetic acid PCA: paracloro-

Introduction It is well known that the central monoamines play a role in the control Of ingestive be havior and there is evidence that anorectic drugs may decrease food intake by interacting with brain monoamines, at least in experimental animals.Furthermore biogenic amines appear to be differentially involved in the anorectic activity of these drugs. The purpose of this paper is to surenarize on food intake and biogenic amines in rats. Materials Experimental

the effect

of several

anorectic

drugs

(Fig.

1)

and Methods

conditions

The anorectic response was measured in rats. Groups of 5 adult Long Evans rats were traimd to eat their food between 09.00 till 16.00 each day and the amount eaten after 2 and 7 h were recorded. Water was available at all times.

341

342

J.

Duhault

et

al.

OH

cH2-

Cy-CH3 NH2 MAZINDOL

AMPHETAMINE

c"2 -

"1" -cH3 NH-C2H5

FENFLURAMINE

QUIPAZINE

oO“Y0

H2-CH-CH3 I NH2

0

cF3

LILLY

NOR-FLUTIOREX

110-140

cF3 H-CH2-NH-CH2 I OCH3 MK 212

SKF

1 - 39728

0 -0

A

@O&CH2-C;-CH3 NH2 LB1

Fig.

1.

Chemical

S 7342

80

structures

of

some

anorectic

drugs.

Anorectic

drugs

and

All drugs were injected intraperitoneally. before food presentation. Pretreatment (saline of the feeding period. Inhibition of feeding expressed as percent of food consumed during with food intake of rats injected with saline, Experimental In vitro according (Belin et

brain

343

monoamines

Anorectic drugs were always administered 30 min or others) was given 60 min before the start in the 2 h following food presentation was the same time the preceding day and compared tested simultaneously.

technique synaptosomal to Gray and al., 1976).

uptake Whittaker

: brain (1962).

synaptosomes Incubations

In vivo synaptosomal uptake : synaptosomes Ten days before sacrifice, some rats were dihydroxytryptamine creatine-sulphate (5,6 stereotaxic apparatus under light Nembutal controls.

were were

isolated pretreated DHT) in anesthesia.

prepared performed

from the mesencephalon as previously described

from drug treated rats were used. by one injection of 75Pg of 5,6 20 ~1 into the lateral ventricle using Sham operated animals were used as

a

In another set of experiments co trol group and 5,6 DHT pretreated rats received one intraperitoneal injection (I.P.) of 1I4Cf fenfluramine (5 PCi) and unlabelled fenfluramine (25mg/kg) in saline. Animals were killed 2 hours later, and the hypothalamus and mesencephalon were removed and dissolved in Soluene 350. The radioactivity was measured with a Packard spectrometer.

Results

and

Discussion

Table 1 shows the reduction in food intake induced by anorectic drugs and serotoninergic reagentsin saline pretreated rats. Clomipramine administered 30 min before tested drugs, significantly abolished the food suppressant effect of fenfluramine only. The 5-hydroxytryptamine precursor (5 HT), 5-hydroxytryptophan (5-HTP), potentiated the anorectic effects of amphetamine and Lilly 110-140. Pretreatment with dibenamine, an a-adrenoceptor blocker, slightly antagonized the effect of amphetamine, fenfluramine and nor-flutiorex. Pimozide, a dopamine receptor blocking agent, markedly antagonized the anorectic potency of d-amphetamine, mazindol and nor-flutiorex, thus significantly increasing the ED 50 values, whereas fenfluramine activity was not significantly altered. The new compound MK 212 and fenfluramine exhibited anorectic response to MK 212 was not affected by prior other pharmacological tools, Paraphenoxy derivatives to reduce food consumption in rats.

Anorectic activity pharmacological

(ED agents.

: mg/kg

50

i.p.)

of

Table

1

drugs

in

Clomipramine

keh;gtamine

1.34

> 25 0.27

Mazindol Quipazine ;e;$U;ramine

2.11

Lilly 110-140 Nor-flutiorex MK 212 SKF l-39728 A :ach value :D 50 values

is

the were

1.95 > 25 4.57 1.02 2.31 6.95 mean of calculated

6 determinations. according

similar anorectic administration of amphetamine

rats

30 min

5OH-Tryptophane

after

activity but clomipramine and fenfluramine

the

of

treatment

Dibenamine

or failed

with

several

Pimozide

1.08

0.97

2.27

4.32

0.20 2.05 > 10

0.30 1.15 1.72

0121

1.21

2.40

2.25

1.12 2.10

0.95 1.86

1.38

1.72

2.42

1.97

c

1.80

to

Litchfield

and

Wilcoxon

344

J.

et al.

Duhault

Table Influence by carotid

of

anorectic section 2,5

drugs h after

on midbrain 5-HT drug administration.

Name

7342 LB1 80 MK 212 SKF l-39728

*

p <

of

5-HIAA

10 20 20 20 :i

in

CONC;;;,"AiICI;

Dose mg/kg i.p.

Saline Fenfluramine Nor-flutiorex

Groups

and

I

Drugs

2 rats.

IN

5 HT

All

animals

BRAIN

(wet

were

tissue)

5 HIAA

0.48 + 0.003 0 32.2 0.02

0.72 + 0.03 0 58.2 0 03

0'3o*f 0:50 f 0.47 + 0.43 +

0'41*+ 0:79 + 0.85 + 0.75 + 0.65 +

0.51

sacrificed

0 02 0:01 0.01 0.03

+ 0.02

0'05 0:07 0.06 0.07 0.03

5 animals

0.01

As shown in Table 2, fenfluramine and nor-flutiorex, of brainserotoninand brain 5-hydroxy-indolacetic with no anorectic activity failed to modify brain The relative potency of fenfluramine tosomes is shown in Table 3. Fenfluramine respectively) but less potent than Lilly Drugs effects in vivo situations of in vitro There was a significant sacrificed 4 hours after tion (Table 4).

and

acid 5-HT

unlike in the content.

MK 212, decreased rat. The phenoxy

MK 212 as inhibitors of and MK 212 were equiactive 110-140 or clomipramine.

on the uptake of different neurotransmitters high affinity uptake (initial extracel ular inhibition of the in vitro uptake of t 14~1 fenfluramine, Lilly 110-140, or amphetamine

5-HT uptake (Ki : 1.6

the levels derivatives

in brain 10-6 and

synap10-6 M

were also stiddicd in concentration below I PM). 5-HT when rats were intraperitoneal injec-

The binding of l4 C fenfluramine (in terms of radioactivity) was determined in two specific areas of the rat brain, 2 hours after i.p. injection of 5pCi of labelled compound in 25 mg/lg fenfluramine. Table 5 shows that radioactivity was higher in mesencephalon than in hypothalamus. However, pretreatment with S,6 DHT decreased the binding of radioactivity to the hypothalamus (30 %) more than the binding to mesencephalon (15 %). Since fenfluramineelicited anorexia was decreased by destroying nerve terminals with 5,6 DHT, it could be suspected that the uptake mechanism is required at the level of neuronal membranes. In fact, in such pretreated animals, Table 6 shows a significant decrease of[I4C] 5 HT (50 %) and of [14C] fenfluramine (20 %) uptake by synaptosomes, as compared with controls. In conclusion, our findings are compatible With the existence of a serotoninergic system regulation food intake in rats. However there is evidence to implicate other central monoamines in ingestive behavior. Catecholamines play an important role in the decrease in food intake induced by amphetamine, phentermine and diethylpropion, whereas like amphetamine, mazindol appears to reduce food intake through a mechanism also involving brain dopamine as their anorectic activity is antagonized by pimozide (Table 1). Mazindol and amphetamine inhibit DA and noradrenaline uptake by mesencephalon or striatum synaptosomal preparations (Table 4) and provoke dopamine release (Table 7). MK 212 did not significantly affect DA uptake and release by synaptosomes.

Anorectic

Relative

potency

of

fenfluramine

drugs

and

and

brain

Table

3

as

inhibitor

MK 212

monoamines

of

5 HT uptake Relative

IC 50

Drugs

Fenfluramine

2.2

10-6M

2.5

10-6M

Lilly

of

4 determinations.

potency

x 10-3

of

anorectic

drugs

on

neurotransmitter

0.5

Drugs were Numbers in mg/protein/min. * pco,o5

injected brackets

25 10 mg/kg 5 mg/kg

IP IP IP

1 mg/kg

IP

4 h before represent

of

P4C]

uptake

- 5 HT dM

in

vivo,

by

14C

1

+ +

1* 1*

95

f

1

as

brain

65

(groups expressed

of

synaptosomes.

- DOPAMINE 1-M

100 + (0.021) 85 + 97 + 60 t

2*

75 88

the Sacrifice control values

fenfluramine

2 500

-

100 + (0.023) 14 +

100

4

Table Binding

400

11

4 10-8M

i4C

Fenfluramine Lilly 110-140

454

9 10-8M

Table

Effects

synaptosomes.

mg/k 110-140

Clomipramine Mean

brain

1 IC 50

MK 212

by

f

14C

1wM

3

2 2 2* 3*

4 rats). in nM of

- NOREPINEPHRINE

transported

100 +

4

(0.027) 92+

2

60:

6*

62 f

4*

compound

5

percent

Of controls.

, Groupes Control 5,6 Values in brackets 5,6 DHT (8 rats) control (8 rats) Both

groups

received

represent : 7511 g in : 511 Ci

DHT PJ 20111,

Mesencephalon

Hypothalamus

fenfluramine intraventricular intraventricular fenfluramine

100 + (0.028)

3

72+

2

100 + (0.0-35) 85+

(UCi/g wet injection injection. i.p.

3

(in

2

tissue). 10 days

25 mg/kg

before

unlabelled

sacrifice compound),

346

J. Duhault

et al.

Table

6

to synaptosomes 14C Fenfluramine and p4 C] 5 HT binding treatment, expressed as percent of controls.

in

vitro,

[14C]Fenfluramine 20 IJM

Groups

Controls

100

10 days

P4CI

Values in brackets 5.6 DHT (8 rats) Controls

(8

rats)

DHT

represent 75 Ug : 20 ~1

:

labelled in 20~1, saline,

+ 2

compound intraventricular

Release

of

fl

I4 C

DA from

rat

10-g 10-8 lo-'

5.10-7 lo-6 5.10-6 10-5 10-4

* p *

0.05

( llM/mg injection

intraventricular

neostriatal

Increase Dose

48

bound

+ 3,3

protein/min) 10 days

before

injection

Table

7

synaptosomes

after

anorectic

drugs.

- in

[14C-JDA

Fenfluramine

release.

% of 1

controls

Amphetamine

4.5

11 9.3

3.6

12.9.

7.95

7.7 0

7.7

3

30.4. 36.6. 48.5'

16.2. 34.2*

OHT

100 + 2 (0,017)

+ 5

82

5,6

5 HT PM

0.42

(2,301 5,6

after

6.2

sacrifice

Anorectic

drugs

and

brain

monoamines

Fenfluramine d&d not modify release of DA at lower concentrations whereas at 10 M DA release was significantly higher thanincontrols the same experiment. These results suggest the possibility of nergic system after high doses of fenfluramine. The results presented above confirm drugs act through different mechanisms involved in control of feeding behavior.

and extend previous , and illustrate

that

an

observations several

347

(5.10W7# run influence

and 10T7 M) simultaneeusly on the dopam+

that various neurotransmitters

in

anorectic are.

The importance of catecholamines in the regulation of feeding processes has heenrecogntzed for over 20 years, but the role of the serotoninergic system was more recently suspected, As is well known in the rat, intraventricular injection of noradrenaline stimulates rather than inhibits feeding, and a substance stimulating central a adrenoceptors (cloni'dine) also stimulates feeding in rats. This effect is antagonised by aadrenoceptor blockin agents (Le Oouarec et al., 1972). Therefore, noradrenergic mechanisms are unlikely to p %ay a major role in mediating anorectic responses to drugs. As previously reported (Kruk, 1973) activation of dopamine receptors by direct application of dopamine, or with a direct receptor agonist, apomorphine or pirlibedfl, produced anorexia. Pimozide, a dopamine receptor blocker, antagonized the anorectic effect of these drugs and suggested involvement of the dopaminergic system in the regulation of food intake. On the other hand, according to Kruk (1973), intraventricular injection of 5-HT inhibits food iintake, and Blundell reported anorectic activity of the serotonin precursor 5-HTP (Blundel and Lesham, 1975). Such an effect is blocked by pretreatment with the 5-HT antagonists cyproheptadine ormethysergide. These observations suggested the existence of a serstonfnergic system regulating feeding center activity. Arising from this possibility, serotontnergic agonists could be active in reducing food consumption and the activity of some anorecttc agents could be mediated by the 5-HT system. A number of recent studies supports the hypothesis that 5-HT is involved in the anorectic action of fenfluramine (Jespersen and ScheeilKruger, 1973, Ghezzi et aZ., 1973, Duhault 19751. Metheraoline (Funderburk et ~2.. 19711 and CvDroheDtadine (Kruk, 19731 were reoorted to antagonize-the anorectic properties-of fenfluram%e, but conflicting resuits were re orted after methysergide pretreatment (Blundell and Lesham, 1975, Schmitt, 1973), pro6ably re P ated to the delay after antagonist administration. As shown in the present study, the reduction in food intake induced by fenfluramine was not antagonized by an a adrenoceptor blocking agent (dibenamide) or dopamine-receptor blocking agent (pimozide), but clomi‘prami'ne administered 30 min before fenfluramine reduced the anorectic effect of this drug only. Interestingly enough, Lilly 110-140 and to a lesser extent quipazine, potentiate the anorecttc effect of 5-HTP but only Lilly 110-140 has additive effect with fenfluramine. Fenfluramine activity through a serotoninergic system was supported by investigation on the synaptosanal uptake. As revealed by d b e reciprocal plots, fenfluramine pretreatment competitively-6 inhibited the uptake of[ a C 1 5 HT for an initial concentration between 0.1 and 0.5 x 10 M. The apparent Michaelis constant is 0.116 + 0.006 x lo-6M for the control group and 0.2192 0.037 x 10-6 for the fenfluramine treated group (Duhault et al., 1978). In vivo experiments confirm that fenfluramine is a competitive affinity uptake of 5-HT into brain synaptosomes. Fenfluramine selective inhibitor for 5-HT uptake, Lilly 110-140. Similarly, ted the reuptake process in synaptosomes (Hamon et al , 1976) serotoninergic terminals as suggested by the lack of inhibition

inhibitor of the high shares thts activity with a quipazine competitively i'nhi%iand had direct effects en of clcmipramtne pretreatment,

The functional integrity of the serotoninergic system is required for fenfluramine actl+fi'ty since parachloroamphetamine, a 5 HT neurotoxin, has been reported to produce a long lasting depletion in brain serotonin and a decrease of the anorecti'c activity of fenfluramine l'n rats (Ouhault and Boulanger, 1977). Such a neurotoxic effect was suspected by Harvey et at., 1977, after acute fenfluramine administration. Fenfluramine was shown to have less of an effect than PCA on brain 5-HT, of shorter duration (Duhault and Boulanger, 1977). On the other hand, no neuronal abnormality or glial reaction was observed in the brain (B 8 - B 9 areas) of rats sacrificed either after acute administration or cumulative doses of fenfluramine (OliVfer et al., 1978 : Lorez et al., 1978). Since we failed to reproduce the findings of Harvey (dark neurones and perineuronal spaces enlargement) in the B 9 area of the brain of fenfluramine treated rats, it is suggested that these neurotoxic aspects are related to a fixative artefact as reported by Cammermeyer (1962).

343

J. Duhault

et al.

A new anorectic compound, MK 212 (Clineschmidt et UZ., 1977) acts mainly via the serotonibut fails to decrease brain 5 HT. On the other hand, nergic system, resembling fenfluramine, the anorectic action of MK 212 was antagonized by prioradministration of methergoline or 1978), but in rats previously treated with clomipramine cyproheptadine (Clineschmidt et al., the activity of MK 212 was unaffected. In this respect, MK 212 differs from fenfluramine and could be suspected as a direct serotonin-mitrectic agent, at least in certain brain areas. The integrity of neuron systems projecting into or passing through the hypothalamus has Intraperitoneal injection of d-amphet been shown to be essential for food intake regulation. amine or mazindol causes a dose dependent decrease in the food eaten in the 2 h following presentation. Their anorectic effect was abolished following pretreatment with pimozide 30 min before the anorectic agent. Neither clomipramine nor 5 HTP significantly affected feeding responses, whereas dibenamine slightly reduced amphetamine potency only. Both anorectic drugs were potent inhibitors of dopamine and norepinephrine uptakes. These results were consistent with those presented by Krug and Zarrubdast (1976) indicating that amphetamine and mazindol were more potent as inhibitors of uptake than as releasers of monoamines. In addition, since stimulation of dopamine receptors with a direct receptor agonist (Barzaghi et ~2, 1973) produced inhibition of food intake, we re-emphasize that activation of dopamine receptors can mediate anorectic responses to some anorectic drugs. Conclusion To conclude, the mechanism of action of anorectic drugs appears more complex than previously increases and decreases in central dopaminergic activity can reduce feeding suspected : both and experimental results support the hypothesis of the noradrenergic function in the regulation of food intake. The involvement of serotonin systems in feeding is well established (Blundell 1977) but observations suggest that the tryptaminergic system might regulate the activity of Awazi and Guidberg, 1978)) therefore alteration dopaminergic neurons (Fuenmayor-T, 1978, of functional activity in the 5 HT systems after anordic drugs could modify the balance leading to an inhibitory effect on feeding. between dopamine or noradrenaline and serotonin,

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BARZAGHI, F.,aPPETTI, A., MANTEGAZZA, P. and MULLER, E.E. (1973) Reduction of food intake by apomorphine, a pimozide sensitive effect. J. Pharm. Pharmac. 25 : 909-911, BELIN, M.F., KOUYOUMDJIAN, J.C., BAROAKDJIAN, J., DUHAULT, J. and GONNARD;-P. (1976) Effects of fenfluramine on accumulation of 5-hydroxytryptamine and other neurotransmitters into synaptoscmes of rat brain. Neyoptiacolpgy 15 : 613-617. BLUNDELL, J.E. and LESHAM, M.B. (1975) Biphaslc a%ion of a 5-hydroxytryptamine inhibitor on fenfluramine-induced anorexia. J. Ph. Pkarmac. 25 : 492-494. BLUNDELL, J.E. (1977) Is there a role for serotonin Fhydroxytryptamine) in feeding ? Intern. J. Obesity 1 : 15-42. CAMMERMEYER, J. (1962r An evaluation of the significance of the "dark" neuron. Rev. Anat. Embryol. Cell Biol. 36 : 1-61 CLINESCHMIDT, B.V., HANmN, H.M., PFLUEGER, A.B. and MC GUFFIN, J.C. (1977) anorexigenic and ancillary action of MK 212 (6-chloro-2-l-piperazinyl-pyrazine ; CPP). i%ychophamtlacology 55 : 27-33. CLINESCHMIDT, B.V., MC GUFFIN, J.C., PFLUEGER, A.B. and TOTARO, J-A. (1978) A 5-hydroxytryptamine-like mode of anorectic action for 6-chloro-2-lpiperazinyl-pyrazine (MK 212). BP. J.

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