Dopamine agonists used in the treatment of Parkinson's disease and their selectivity for the D1, D2, and D3 dopamine receptors in human striatum

Prqq.Nrllro-Psychopharmacol. Pergamon

& Bid. Psychiat. 1995. Vol 19. pp. I 147-I 154 Copyright 0 1995 Elsevier Srienre Inc. Printed

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DOPAMINE AGONISTS USED IN THE TREATMENT OF PARKINSON’S DISEASE AND THEIR SELECTMTY FOR THE D1, D,, AND D3 DOPAMINE RECEPTORS IN HUMAN STRIATUM JACQUES DE KEYSER*, JEAN-PAUL Department

of Neurology,

Academisch

DE BACKER, NADINE WILCZAK Ziekenhuis Vrije Universiteit

and Luc HERROELEN

Brussel, Brussels, Belgium

(Final form, June 1995)

De Keyser, Jacques, Jean-Paul De Backer, Nadine Wilczak and Luc Herroelen: Dopamine agonists used in the treatment of Parkinson’s disease and their selectivity for the DT , D2, and D3 dopamine receptors in human striatum. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1995, 1 g(7): 1147-l 154.

1.

2.

3.

4.

It has been suggested that an ideal antiparkinsonian treatment requires stimulation of both D1 and D2 dopamine receptors. Bromocriptine and lisuride are regarded as pure D2 receptor agonists, whereas pergolide and apomorphine are thought to stimulate both DT and D2 receptors. The aim of this study was to compare the affinities of bromocriptine, lisuride, pergolide, and apomorphine for the DT , D2, and D3 receptors in postmortem human striatum. The dissociation constants (Ki values) of the dopamine agonists were determined from competition binding experiments with selective radioligands. The Ki values of the orally administered agonists - bromocriptine, pergolide, and lisuride - for the D2 receptors were proportional to their optimal doses against parkinsonism. Ki(DT )/Ki(D2) ratios were 23 for lisuride, 67 for pergolide, 60 for bromocriptine, and 2.6 for apomorphine. Ki(D3)/Ki(D2) ratios were 0.4 for lisuride, 1 for pergolide, 5.4 for bromocriptine, and 21 for apomorphine. The present results support the hypothesis that the antiparkinsonian effect of dopamine agonists is mediated primarily by D2 receptors. Apomorphine is a mixed DT /D2 agonist, but pergolide has no more 01 agonist properties than bromocriptine and lisuride. The role of the D3 receptors is unknown, but their activation might either be associated with the generation of psychiatric sideeffects or dyskinesias, or alternatively add to antiparkinsonian activity.

Kevwoa

: dopamine

:

Abbrevlatlons ([3H]SCH

agonists,

dopamine receptors,

human striatum,

Parkinson’s

5-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-l

23390),7-hydroxy-N,N-di-n-propyl-Z-aminotetralin

disease -N-3-benzazepine

([3H]7-OH-DPAT).

Introduction

Striatal Parkinson’s

dopamine

receptors

are the primary targets

disease. Bromocriptine

is only marketed

and pergolide

in European countries

agonists

used in the treatment

are the most widely used dopamine

(Calne, 1993).

* Present address: Janssen Research Foundation,

for dopamine

Apomorphine

Beerse, Belgium

1147

is administered

agonists;

subcutaneously

of

lisuride or


1148

intranasally,

and

Parkinson’s

its

use is currently

disease (Montastruc

Based on a synergistic and non-human combined

to

overcome

sudden

“off’‘-periods

in advanced

et al., 1993).

effect

primates,

stimulation

restricted

c1 al.

of DT and D2 dopamine

it has been proposed

of both DT and D2

that

dopamine

receptor

agonism on locomotor

an ideal antiparkinsonian

receptors

(Walters

activity

treatment

et al., 1987;

in rats

requires

Gomez-Mancilla

a et

al., 1992). Traditionally, pergolide

bromocriptine

and lisuride

and apomorphine

Montastruc

et al.,1 993;

provide

a better

versus

DT /D2

are considered Beaulieu,

therapeutic receptor

are regarded

1987;

response

stimulation

to stimulate Ahlskog

as pure both

than bromocriptine

is based on measurements binding

receptors

in tissue culture

cells (Goldstein

et al., 1980;

agonist-induced

dyskinesias

have also suggested

receptors

(Ahlskog

localized

within

Landwehrmeyer

that

et al., 1992; the

limbic

et al., 1993;

Rosengarten

et al.,

on receptors

1983).

system,

including

the

Herroelen

et al., 1994),

whereas

(Came,

thus

activity

may result

from

receptors

in rodent

Studies

activation

of DT

are preferentially

(Sokoloff

and their activation

in D2

animal brain and cloned

Seeman & Van Tol, 1993).

striatum,

1993;

theoretically

the distinction

cyclase

from

D3 dopamine

ventral

could

However,

of adenylate

and radioligand

expressed

Pergolide

and lisuride.

experiments

agonists,

DT and D2 receptors

et al., 1992).

brain homogenates,

in animals

D2 receptor

et

al.,

1990;

might contribute

to drug-

of bromocriptine,

lisuride,

induced psychosis. In this study pergolide,

the authors

have compared

the pharmacological

specificity

for the D1 , D2, and D3 dopamine receptors

and apomorphine,

in postmortem

human striatum.

by the ethical committee

of the University

l&sue Preoar~ The use of postmortem

human brain tissue was approved

Hospital of the ‘Vrije Universiteit brains obtained

at autopsy

or psychiatric dopamine

disease,

agonists.

and stored

Postmortem

4°C in 50 mM Hepes/NaOH

were determined

[3H]SCH benzazepine)

23390

nucleus and putamen)

None of the patients

containing

had received

1 mM EDTA, and centrifuged

and centrifuged

containing

twice at 30,000

10% glycerol

(vol/vol),

were dissected

years) without

from

neurologic

antipsychotics

were homogenised

at 30,000

or at

g for 20 min.

g for 15 min. The final pellet and stored

at -80°C.

Protein

by the method of Lowry et al. (1951).

(5-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-l-N-3-

and [3H]7-OH-DPAT

from Amersham.

at -80°C.

in buffer

in the same buffer

concentrations

(caudate

(5 men and 3 women; aged 46-82

delay was less than 12 hours. The pooled striata

(pH 7.5)

The pellets were resuspended was suspended

Brussel’. Striata

from 8 patients

[3H]spiperone

(7-hydroxy-N,N-di-n-propyl-2-aminotetralin)

was obtained

from New England Nuclear. Bromocriptine

were

obtained

was a gift from

Dopamine agonists and human striatal dopaminr Sandoz,

pergolide

the Janssen

from

Research

Eli Lilly, lisuride from Schering, Foundation.

Apomorphine,

mianserin

(+)butaclamol,

1149

receptors

from

Organon,

and dopamine

and spiperone

from

were purchased

from

Sigma.

The DT receptors

were studied

with [3H]spiperone

with

[3H]SCH

23390

(De Keyser et al., 1989b),

(De Keyser

et al.,1 989a),

and the D3 receptors

the D2

receptors

with [3H]7-OH-DPAT

(Herroelen

et al., 1994). The striatal 23390

(87

membranes CVmmol)

at a final concentration

or [3H]spiperone

mM MgCl2 for 20 min at 30°C 7.5), containing Saturation

experiments

between

1 nM. For competition

[3H]SCH

23390,

0.5

and that

samples

were rapidly

filtered

a Beckman (LS 6000)

the following

0.3 mM was added to prevent

were

performed

6 concentrations

concentrations

(pH

adrenergic

receptors

6

with

of

[3H]SCH

(De Keyser et

0.3 I.IM mianserin

of 4 ml of ice-cold

GF/B glass fibre

with between

were used: 2 nM for Binding

of 100 nM spiperone

by the addition

over Whatman

filters.

buffer.

The filters

The were

remaining on the filters was counted

in

counter. was determined

for [3H]spiperone

pargyline

with

[3H]7-OH-DPAT.

and the radioactivity

23390

and for [3H]7-OH-DPAT

and al

were terminated

buffer,

1989b),

[3H]SCH

in 50 mM Hepes/NaOH

and [3H]7-OH-DPAT [3H]spiperone

and 1 nM for

under vacuum

of [3H]SCH

(De Keyser et al., 1989a),

Pata

23390

to 5-HTz

liquid scintillation

binding

CVmmol)

was masked by the addition

Incubations

washed 3 times with 4 ml ice-cold

Non-specific

[3H]SCH

of [3H]spiperone

(De Keyser et al., 1989b).

(100

with

20 mM NaCI-2

ascorbic acid, for 60 min at 20°C.

[3H]spiperone,

receptors

were incubated

in 20 ml Tris HCI (pH 7.4)-l

[3H]7-OH-DPAT

binding experiments,

nM for

to 5-HTz serotonin

al.,1989a),

with

of 0.3 mg protein/ml

Ci/mmol)

0.2 and 6 nM, and those with

0.05 and

23390

and with

2 mM MgCl2 and 0.005%

binding

concentrations

(81

in the presence

of 10 PM (+)butaclamol

in the presence of 1 PM (+)butaclamol

in the presence of 10 PM dopamine dopamine metabolism)

(De Keyser et al.,

(the monoamine

(Herroelen

oxidase inhibitor

et al., 1994).

Analvsis

Specific binding

binding

studies

was obtained

were analyzed

by subtracting by computerized

non-specific non-linear

constants

(Ki values) of the dopamine agonists were obtained

following

formula:

equilibrium

constant

Ki=ICSO/(

1 +L/Kd),

of the radioligand.

where

binding

from total

least-square

binding.

curve fitting.

from the corresponding

L corresponds

to the

Kd values were obtained

IC50 values by the

concentration

from Scatchard

Competition

The dissociation

and Kd to the

analysis of saturation

binding experiments.

The D3 receptor display

similar

belongs to the DE family of dopamine

affinity

for

cloned

DZ and D3 receptor

receptors, subtypes

and spiperone expressed

has been reported in tissue

culture

to

cells

J. Lk Kryser- (‘I ril.

1150

(Sokoloff

et al., 1990).

To examine

labels D2 receptors,

we performed

spiperone.

displaced

Spiperone

in human striatal concentration

membranes

whether

[3H]spiperone

[3H]7-OH-DPAT

[3H]7-OH-DPAT

agonist competition

only labels D3 receptors, binding experiments,

inhibition of [3H].SCH 23390 Representative competition

[3H]SCH

23390

and [3H]spiperone

a low affinity represents

mediated

et al., 1989b).

presumption (KH=KL)

(Ki=KL).

the receptors

least partially Keyser

state

that

competition

two different

affinity

Only the

that

through

guanine

The monophasic

high- and low-affinity

(Seeman and Van Tol, 1993).

a high affinity

state (Levesque

Ki values of the dopamine Ki(D1 )/Ki(Dz) apomorphine.

ratio

was

23390

curves

state

coupled

nucleotide

with

(Log M)

and of [3H]spiperone (V), pergolide (0))

(2 nM) and [3H]spiperone

pergolide

and apomorphine

a high affinity

state

is pharmacologically

binding

proteins)

for bromocriptine

states

for these

[3H]7-OH-DPAT

agonist,

and

since

it

mechanisms

(at

et al., 1989a;

De

are explained

are identical

is a D3 receptor

(Ki=KH)

relevant,

(De Keyser

and lisuride

agonists

at the

are shown in Fig 1,

to cellular signal transduction

curves

that

or nearly

by the identical

and thus only labels

et al., 1992). agonists

23

The Ki(D3)/Ki(D2)

and 21 for apomorphine.

[3H]SCH

for the agonist:

high affinity

are functionally

unlabbeled

and that [3H]spiperone

binding to DI receptors, curves of bromocriptine

binding

states

selectively

with

only labels D2 receptors.

Dopamine agon~a co~ralion

lisuride (A), and apomorphine (0) for the binding of (0.5 nM) in human striatal membranes are shown.

were biphasic, indicating

membranes

experiments

binding curves for DI and D2 receptors

Oopamine agonistmncantratiin(Log M)

Fig 1. Dopamine agonist binding to D2 receptors.

binding

with a Ki value of 1 PM, indicating

the binding of [3H]7-OH-DPAT

of 0.5 nM, used in the competition

Representative

in human striatal

competition

for

for the 3 dopamine lisuride,

ratio

67

for

receptor

pergolide,

was 0.4 for lisuride,

subtypes 60 for

are listed in Table 1. The

bromocriptine,

1 for pergolide,

and

2.6

for

5.4 for bromocriptine,

Dopamine

agonists

and hl.mxm

striatal

dopaminr

1151

receptors

Table 1. Dissociation

(Ki values) of Dopamine Agonists for DT , Human Striatal Membranes

Constants

D2 receptors (nM)

D1 receptors (nM) bromocriptine lisuride pergolide

2170?416** 83? 9 ** 230 + 26 (43 f 2) 3130+ 91 48 f 4 (45 f 3) 1620f 76

KH (46/?/f) KL KH (%RH) KL

apomorphine

D2 and D3 Dopamine Receptors in

36 3.5 3.4 113 18 480

f 3** ?r 0.6 ** * 0.5 (52_+ 2) rt 26 f 3(49_+2) f 30

Values are the means + SD of 4 experiments

carried out in duplicate.

respectively

state

the high and low affinity

agonist

D3 receptors (nM)

of the receptor.

*

197 f20 1.6 + 0.1 3.4 t 0.2 389

+

4

KH and KL are the Ki values of *

[3H]7-OH-DPAT

only

labels

a

high affinity state of the D3 receptor;** KH = KL. (Ki values (dissociation constants) are the reciprocal of the affinity of a compound for a receptor. The lower the Ki value, the higher the affinity or potency. RH is the number of high affinity sites.

Bromocriptine lisuride

displayed

had a lo-fold

a higher affinity

higher

affinity

keeping with the clinical experience than

bromocriptine

receptor

(Calne,

is the primary

agreement

with

a previous

agonist/antagonist clinical potency

An important

receptors

(lower

Ki value)

et al., 1993;

in which

in human

cannot

brain.

motor

comparable

Gomez-Mancilla

affinities

and bromocriptine traditional appears adenylate 1980).

respectively

incorrect. cyclase

et al., 1992).

The relevance

(Dl

patients

agonists.

responses

(Schachter

to general thoughts, Very

the antiparkinsonian

In our study,

of such findings

that

is known

pergolide,

is doubtful,

efficacy

a 23-fold

lower affinity

stimulation)

models

apomorphine

Lisuride displayed

a 60 and 67-fold

receptor

little

in rats and primate

provides a more balanced D1 /D2

It has been reported activity

contrary

experiments

at DT and D2 receptors.

view that pergolide

it is likely that

to dopamine

endocrine

bromocriptine.

In

10 times more potent

to

the D2

This is in

D1

and D2

et al., 1980).

with the other three dopamine

and lisuride.

suggest that selective D1 agonism may potentiate et al. , 1987;

and

1987),

than

Pergolide and

agonists,

The

because

or intranasally.

bromocriptine

However,

Beaulieu,

response

in parkinsonian

be compared

from this study is that,

than

D2 receptors

Montastruc

of the antiparkinsonian

subcutaneously

conclusion

for these

and lisuride being approximately

drugs were investigated

properties

than at DT and D3 receptors.

of pergolide

study

of apomorphine

this drug is administered

D1 agonist

1993;

mediator

at D2 receptors

pergolide about

has no more

the

role of D1

of Parkinson’s

disease

of D2 agonists

(Walters

was the only agonist

showing

lower affinity,

and pergolide

at D1 than at D2 receptors. agonism than bromocriptine

unlike bromocriptine

in rat striatal since striatal

and lisuride,

homogenates homogenates

Thus the or lisuride

(Goldstein contain

enhances et al.,

a mixture

of

.J. DC Kqser

1152

receptors

which may influence

adenylate

cyclase

<'Icd

activity,

including

binding studies in animal tissue and cloned human dopamine pergolide for the high affinity

states of the D1 and DZ receptors

Van Tol, 1993).

there

(Creese

However,

et al., 1979),

for the corresponding results

is that

disease both

receptors

pergolide

(LeWitt

agonists,

and that

patients

(Sokoloff

in the way that

long-term

et al., 1990).

efficacy

require

of parkinsonian

disability,

&

bind agonists

identical to those

Consistent

in improving

with the present

features

of Parkinson’s

when used in monotherapy

I-dopa as an adjunct

of both D1 and Dz receptors

Previous

nM) (Seeman

receptors

are not necessarily

than bromocriptine

eventually

D2 receptors.

have shown that the Ki values of

were similar (KHxO.8

for cloned receptors

in native tissues

et al.,1 983), as most

improvement

species differences

affinities

is no more effective

Because a balanced stimulation optimal

exist

and agonist

inhibitory

receptors

is limited

for

et al., 1991).

(Caraceni

may be required to achieve and sustain an

the addition

of I-dopa may be necessary

to coactivate

D1 receptors.

0

or the Trnt Bromocriptine

of Parkinson s Dlsea

has a lower incidence of dyskinesias

al., 1993).

The finding

hypothesis

that activation

dyskinesias,

that

both

agonists

of D1 receptors

as has been suggested

is the main mechanism

from animal experiments

In both rat and human brain, D3 receptors and other implicating

limbic areas (Sokoloff a possible

are enriched

et al., 1990;

role in mental

and emotional

than bromocriptine

at D3 receptors

related,

and it may be possible that the activation

effects

of dopamine

agonist treatment.

agonists

the D1 and D2 receptors, 1994).

Bromocriptine,

and D3 receptors, efficacy

D3 receptors

implicating

exposed

Therefore,

genesis of dyskinesia.

functions.

Psychotic

coactivation

showed

side-

are not restricted

D2

to the

similar to that of

as well (Herroelen

et al.,

when given to animals or

has a 5-fold lower affinity activation

of D3 receptors

a higher

are dose-

when more selective

properties

D3 receptor

accumbens)

On the other hand, the authors

function

in view of the similar high affinity

et the

et al., 1994),

to the psychiatric

the whole striatum

role in motor

it may be possible that

(nucleus

manifestations

contributes

throughout

BBdard against

agonist-induced

Herroelen

labelled by [3H]7-OH-DPAT

a possible

we cannot exclude that

striatum

will only be confirmed

to I-dopa (BBdard et al, 1993),

Alternatively,

dopamine

Lisuride and pergolide

of D3 receptors

distribution

argues

et al., 1983).

et al., 1993;

which stands out as having little dyskinetic

humans not previously for DE receptors.

in the ventral

and apomorphine.

This hypothesis

but show a widespread

et al., 1992; ratio

mediating

will become available for studies in humans.

have found that in human striatum, nucleus accumbens,

(Ahlskog

(Rosengarten

Landwehrmeyer

affinity

and D3 receptor

than pergolide

share a similar Ki(D1 )/Ki(DZ)

for D3 than

is associated

of pergolide

with

the

and lisuride for D2

may add to the antiparkinsonian

of these agonists. These questions can only be answered when selective

D3 receptor

agonists will

become available for studies in humans. It is expected properties differences,

that

or with

new agonists very

high

and that agonist

are not necessarily

will be developed

selectivity. affinities

with either combined

It is important

for cloned dopamine

identical to those for the corresponding

to

emphasise

receptors

receptors

dopamine that

expressed

receptor

there

exist

subtype species

in tissue culture

in native tissues.

cells

To obtain a more

1 15.3

Dopamine agonists and human striatal dopamine receptors accurate

insight in the functional

also include research

receptor

binding

aimed at unravelling

will be of great

properties studies

of dopamine agonists,

in

postmortem

the functional

human

pharmacodynamic brain tissue.

roles of the different

help for the design of new dopamine

agonists

receptor

with

better

evaluations

It is likely subtypes efficacy

should

that

future

in human

brain

and less adverse

effects.

Our results support primarily

the hypothesis

by D2 receptors.

properties receptors

than

that the antiparkinsonian

In human striatal

bromocriptine

membranes,

and lisuride.

Pergolide

effect

pergolide

of dopamine

agonists

is mediated

seems to have no more D1 agonist

and lisuride display

a higher

affinity

for the D3

than bromocriptine.

This study

was supported

by a grant

from

the

Belgian

‘Nationaal

Fonds voor

Wetenschappelijk

Onderzoek’

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