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Antipsychotic agents differ in how fast they

come off the dopamine D2 receptors.
Implications for atypical antipsychotic action

Article in Journal of psychiatry & neuroscience: JPN · April 2000

Source: PubMed


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2 authors:

Shitij Kapur Philip Seeman

King's College London University of Toronto


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Antipsychotic agents differ in how fast
they come off the dopamine D2 receptors.
Implications for atypical antipsychotic action

Shitij Kapur, MD, PhD; Philip Seeman, MD, PhD

Kapur Department of Psychiatry, University of Toronto; Seeman - Departments of Psychiatry and Pharmacology,
University of Toronto, Toronto, Ont.
Based on the presentation given by Dr. Kapur on receipt of the Canadian College of Neuropharmacology's Young
Investigator Award for 1999 at the 22nd Annual Meeting of the College, Halifax, June 14, 1999.

Rationale and objective: While the blockade of dopamine D2 receptors are necessary for antipsychot-
ic action, antipsychotic agents differ nearly a thousand-fold in their affinity for the D2 receptor. This affini-
ty is determined by the rate at which the antipsychotic agent binds to (kn) and the rate at which it disso-
ciates from (k.) the D2 receptors. The objective of this study was to determine the relationship between
k.n, k,of and the affinity (K,) of antipsychotic agents for the D2 receptors, with particular reference to typi-
cal and atypical antipsychotic agents. Design: The k. of several typical as well as atypical antipsychotic
agents (nemonapride, spiperone, haloperidol, chlorpromazine, raclopride, olanzapine, sertindole, clozapine
and quetiapine) was measured in vitro using the 3H-radiolabelled analogues of these drugs. The affinity of
these drugs for the D2 receptor was determined by competition with 3H-raclopride in vitro. The k.n was
derived from values of affinity and k,. Main outcome measures: kon, k.,f, and the K, of antipsychotic
drugs. Results: The range of affinity values was similar to that conventionally accepted (0.025-155 nmol/L).
The Kffvalues varied a thousand-fold from 0.002 to 3.013 min-', with relatively little variation in Kn. The
rate at which antipsychotic agents come off the receptor (k.,) accounted for 99% of the variation in their
affinity for the D2 receptor; differences in k., did not account for differences in affinity. Conclusions: The
differences in the affinity of antipsychotic agents are entirely determined by how fast they come off the D2
receptor. These differences in k., may lead to functionally different kinds of dopamine blockade. Drugs with
a higher k.,f will be faster in blocking receptors, and once blocked, will provide more access to surges in
dopamine transmission. Since atypical drugs show a lower affinity and a faster dissociation, a higher kff for
the D2 receptor is proposed as a mechanism for "atypical" antipsychotic effect.

Justification et objectif: Meme si le blocage des recepteurs dopaminergiques D2 est necessaire pour
que les neuroleptiques agissent, l'affinit6 de ceux-ci pour le recepteur D2 differe d'un ordre de grandeur

Correspondence to: Dr. Shitij Kapur, PET Centre, The Clarke Institute of Psychiatry, 250 College St., Toronto ON MST I R8; fax 416
Medical subject headings: antipsychotic agents; clozapine; dopamine; haloperidol; raclopride; receptors, dopamine
J Psychiatry Neurosci 2000;25(2):161-6.
Submitted Nov. 23, 1999
Revised Jan. 19, 2000
Accepted Jan. 21, 2000
2000 Canadian Medical Association

i. iI!,.I
400*kof :I o.-
I.: -:
A., ..
4 Wi 311. mg, 0.4

qui atteint presque le millier. Cette affinite est determinke par la vitesse i laquelle le neuroleptique se fixe (kon)
aux recepteurs D2 et a la vitesse a laquelle il s'en dissocie (k.,f). L'etude visait a determiner le lien entre les fac-
teurs o k,,,f et l'affinit6 (K) des neuroleptiques pour les recepteurs D2 et plus particulierement les neuroleptiques
typiques et atypiques. Conception: On a mesur6 le facteur k,,, de plusieurs neuroleptiques typiques et atypiques
(nemonapride, spiperone, haloperidol, chlorpromazine, raclopride, olanzapine, sertindole, clozapine et quetiapine)
in vitro en utilisant les analogues radiomarques 3H de ces medicaments. L'affinit6 de ces medicaments pour le
recepteur D2 a ete derivee par concurrence avec le 3H-raclopride in vitro. On a d6riv6 la valeur k.o des valeurs
de l'affinite et du facteur k,,O,. Principales mesures de resultats: Facteurs ko.n ko,, et K. des neuroleptiques.
Resultats: La plage des valeurs d'affinit6 ressemblait a celle qui est acceptee habituellement (0,025-155 nmol/L).
Les valeurs k,, ont varie d'un facteur de l'ordre de 1000, soit de 0,002 a 3,013 min-', et la valeur k. a varie tres
peu. La vitesse a laquelle les neuroleptiques se dissocient du recepteur (k,,,) explique 99 % de la variation de leur
affinite pour le recepteur D2. Les differences des valeurs kn n'expliquaient pas les differences d'affinite.
Conclusions: Les differences d'affinit6 des neuroleptiques sont entierement fonction de la vitesse a laquelle ils
se dissocient du recepteur D2. Ces differences des valeurs k8f peuvent entrainer des types differents, sur le plan
fonctionnel, de blocage de la dopamine. Les medicaments qui ont une valeur k8f plus elevee bloqueront plus rapi-
dement les recepteurs et, apres le blocage, assureront un acces plus important aux pics de transmission de la
dopamine. Comme les medicaments atypiques ont une affinite moindre et se dissocient plus rapidement, on pro-
pose une valeur k8f plus elevee pour le recepteur D2 comme mecanisme d'effet neuroleptique (<atypique)).

Introduction constant, which equals k,,f/k.,, allows one to predict

only the equilibrium state of the reaction. On the other
All currently used antipsychotic agents bind to hand, rate constants krn and k.,f allow one to predict not
dopamine D2 receptors, as assessed by their "affinity" only the equilibrium, but also how fast the drug-recep-
or "potency" for the D2 receptor in vitro.',2 Discussions tor system responds to perturbations in the concentra-
of the D2 effects of antipsychotic agents often use the tion of the drug or another competitor. Since the
term "affinity" in a pharmacologic context and "poten- endogenous dopamine levels are not static and are
cy" in a clinical context. Both of these terms usually known to show transient 10-fold increases,5 k,. and k0ff
refer to the equilibrium dissociation constant, K,, or to are more relevant parameters for understanding
the related term K, (which represents the equilibrium dynamic drug action.
dissociation constant measured by competitive inhibi- We were interested in this issue because of the recent
tion). However, Kd or K are hybrid parameters, reflect- findings that atypical antipsychotics are particularly
ing the situation at equilibrium. These parameters are responsive to sudden increases in endogenous dopa-
derived, as shown in the equation below, from 2 more mine and this may confer on them unique clinical prop-
elemental parameters that characterize the dynamic erties.67 Since it is k0, and kff that determine how a drug
essence of drug-receptor interaction. The binding of a responds to sudden changes in concentration and com-
drug to a single receptor is said to obey the simple mass petition, we were interested in determining the k,. and
action law and can be represented as below:3'4 k0ff of antipsychotic agents. In theory, a difference in
either ku,, or k,,f, or both, can be responsible for changes
kon in affinity, and in practice that seems to be the case. For
D+R DR; while Kd -= koff example, atropine has an affinity twice that of methyla-
kon tropinium for the cholinergic receptors; this difference
in K, is driven mainly by differences in their k., with
In this formulation the rate at which a drug (D) binds very similar k., values.4 On the other hand, the 100-fold
to a receptor (R) is determined by the concentration of differences in affinity among 1-blockers are largely
the drug, the receptor and the association rate constant, owing to differences in k., in the face of relatively simi-
k,n (unit concentration-' time-', also called on-rate con- lar kr,, rates.8 Thus, it remains to be established whether
stant). The rate at which the drug-receptor complex DR k.n or k0,, or both, contribute to the differential affinity
dissociates is determined by the concentration of the of antipsychotics for the D) receptors. To our knowl-
complex and the dissociation rate constant, k,ff (unit edge this issue has never been systematically
time-1, also called off-rate constant). Kd, the equilibrium addressed.

0,05,r>raB;Wr q-u
tv-;, .,,
Anisychoti gnt n dopamne rcepors

Methods removed and rapidly filtered at various times at room

temperature. The aliquots were filtered under vacuum
The aim of this experiment was to determine the kon and through pre-soaked glass fibre filters (Whatman GF/B;
k,ff of a series of antipsychotics and relate them to their Brandel, Gaithersburg, Md.) using a Millipore
more commonly measured parameter, Ki, the inhibition (Millipore, Bedford, Mass.) filter manifold. After wash-
constant. As shown in equation 1, since the 3 parame- ing the filters rapidly with 5 mL of buffer, they were
ters are related, determination of any 2 permits the placed in scintillation minivials (Packard, Chicago) and
delineation of the third. Of these, the k,ff and the Ki can were monitored for tritium 6 hours later in a Packard
be determined with greatest accuracy; therefore we 4660 scintillation spectrometer at 55% efficiency. In a
chose to measure these 2 and obtain k,n as a result.9 parallel set of tubes, nonspecific binding of the
[3H]antipsychotic drug was determined in the presence
Tissue of 10 pmol/L S-sulpiride. Each antipsychotic was tested
on 2 or 3 separate occasions.
Rat brains were obtained from Pel-Freez (Rogers, Ark.).
The striata were dissected in the frozen state and homog- Excess raclopride method
enized in buffer (50 mmol/L TRIS-HCl, 1 mmol/L
EDTA, 5 mmol/L KCl, 1.5 mmol/L CaCl2, 4 mmol/L In the presence of the [3H]antipsychotic drug, 18 mL of
MgCl2, 120 mmol/L NaCl; pH 7.4) using a Brinkmann buffer was prepared containing a total of 2 mg of rat
Polytron homogenizer PT-10 (Brinkmann Scientific, striatal tissue to obtain the final concentration listed
Westbury, NY) (5 seconds at setting 5). Pooled tissue below. After 1 hour of incubation at room temperature,
from several rats was used for the determination of kff. 0.5 mL of raclopride was added to give a final concen-
tration of 10 pmol/L raclopride. Aliquots of 2 mL of the
Measurement of k,ff suspension were filtered and counted as in the dilution
method. In a parallel set of tubes, nonspecific binding of
Two methods are widely used to determine kff.34 Both the [3H]antipsychotic drug was done in the presence of
methods rely on measuring the rate of dissociation of the 10 ,umol/L S-sulpiride. Each antipsychotic was tested
radiolabelled ligand over time. In 1 method, dissociation on 2 separate occasions, the results were reliable, and
is initiated by instantaneous dilution, which obviates any the averaged data are presented.
reassociation (the "dilution" method).34 In the other The final concentration of each [3Hlantipsychotic
method, dissociation is measured by the addition of an drug in the 2-mL pre-incubate (dilution method) and in
excess of another antagonist, which competes over- the 18-mL pre-incubate (excess raclopride method)
whelmingly for the same receptor and thereby obviates were identical. These concentrations, chosen to approx-
any reassociation ("excess raclopride" method).9 If the imate the free molarities in the patients' spinal fluid or
receptor-ligand interaction is simply a first-order reac- plasma water phase, were: [3H]nemonapride (100
tion, as characterized by equation 1, then the 2 methods Ci/mmol; New England Nuclear, Boston), 0.2 nmol/L;
should give identical results. On the other hand, if rebind- [3H]spiperone (Amersham), 0.25 nmol/L; [3H]haloperi-
ing or cooperativity are prominent, the interaction would dol (12 Ci/mmol; New England Nuclear), 4 nmol/L;
result in a deviation from first-order kinetics, and under [3H]raclopride (79 Ci/mmol; New England Nuclear), 2
these conditions the 2 methods may give deviant results.34 nmol/L; [3H]sertindole (47 Ci/mmol; H. Lundbeck
A/S, Copenhagen-Valby, Denmark), 5 nmol/L;
Dilution method [3H]chlorpromazine (25 Ci/mmol; New England
Nuclear), 3 nmol/L; [3H]olanzapine (81 Ci/mmol; Lilly
At room temperature for 60 minutes, 1 mL of Research Laboratories, Indianapolis), 5 nmol/L;
[3H]antipsychotic drug and 1 mL of rat striatal tissue [3H]clozapine (84 Ci/mmol; New England Nuclear), 10
(final = 2 mg tissue/mL) were incubated to achieve the nmol/L in the presence of 300 nmol/L clozapine;
final antipsychotic concentrations listed below. After 1 [3H]quetiapine (14 Ci/mmol, custom-prepared by New
hour, 16 mL of buffer was added, and the resulting mix- England Nuclear), 10 nmol/L in the presence of 200
ture was stirred to provide instantaneous dilution. nmol/L quetiapine. The time intervals over which the 8
Eight aliquots of 2 mL of the resulting suspension were measurements were distributed were different for dif-

Vol. 25, AO
yo...1.1.25. no 2,2000
2' 2-W

Journ4 oE Psychiatry AN
& Neurosdence .1ls
ferent antipsychotics and were decided on the basis of od. The results were highly correlated (Pearson's correla-
preliminary experiments to provide an optimal esti- tion coefficient 0.98, p < 0.0001); therefore for further cal-
mate of rate of dissociation (e.g., samples every 10 sec- culations we pooled the data from these 2 methods.
onds for [3H]clozapine to every 30 minutes for The k,ff values of the available antipsychotics varied
[3H]nemonapride). In each case the specific binding at almost 3 orders of magnitude, from a very slow dissoci-
time zero was taken as 100%, and the effect of dilution ation constant of 0.0024 min-1 for nemonapride to 3.1
over time was plotted to obtain the time for 50% decline minw1 for quetiapine. The kn. values showed relatively
in binding (t1l2). Since t112 = 0.693/k,ff, k,ff was deter- less variation, from 10.6 nmol/L-l min-' for nemon-
mined from the measured t12 as 0.693/t1l2. apride to 166 nmol/Ll1min-l for olanzapine. The Ki val-
ues were consistent with those reported previously.
Measurement of Ki Most importantly, the Ki values were very highly pre-
dicted by k,f (F1,7 = 1656, p < 0.0001) (Fig. 1), and showed
The details of the method for the determination of K no significant relationship with kon values (F1,7 = 0.05, p
have been presented in detail previously.2 Briefly, the = 0.829). The differences in the k., of the antipsychotics
long form of the D2 receptor was stable expressed in explained 99% of the variance in their affinity for the D2
GH4Cl cells.10 Cells were collected and suspended with- receptors, whereas differences in kon do not meaningful-
out washing or centrifugation and were homogenized ly relate to differences in affinity.
(5 seconds at setting 5 in a Brinkmann Polytron homog-
enizer PT-10) to yield approximately 200 ug/mL pro-
tein. [3H]raclopride, the membrane suspension and 100 /
* Quetiapine
unlabelled antipsychotic of interest were coincubated in
1.5 mL buffer with the final concentration of raclopride
fixed at 2 nmol/L, the receptor concentration at 10 10
Olanzapine *
pmol/L and with varying concentrations of the anti-
psychotic for which the K, was to be determined. The Ki
Raclopride.* ndole
1 Chlorpromazin
Y FAaloperidol
was calculated from the IC., concentrations using the
Cheng-Prusoff formula1" and a value of raclopride Kd of Spiperone
1.6 nmol/L, obtained as described previously.2 0.1 0

Results 0.01 I
0.001 0.01 0.1 1 10

The detailed results are presented in Table 1 and Fig. 1. koff (min")
We did not find any significant differences (paired t-test, Fig. 1: The relationship between the equilibrium constant
tdf7 = 0.925, p = 0.382) between the tl/2 determined using K,(units of concentration) and the dissociation rate con-
the dilution method or using the excess radopride meth- stant k.. (units of time) for a series of antipsychotics.

| : . r S .'1-bX g ; j;< 3 11

rf .sf s - o5 .r ..
20O '.'2
Mr.;t 1~~~~~~~~~~~~~~~~~~~A 1

YIMM 2i i Wi
0*17^) 8
|x*-- ~ § ; .r dd.

sl .il
;_ | 5. t. j..;E fi tr..LJ eS
t5l .: ElLJ H;' -i-V Ft 8 2 l~t.
_ t "'I.,~~~~~~~~~~~~~~~~~~~~
"A I',' -.
ii '.
- W i. ii, I . -- .. - - m . .. -- ... ---, -,-- .. -t '. --. 'L. -- .

Antipsychotic agents and dopamine receptors

Discussion agents showed a much higher affinity for the D2 recep-

tor (pKi 8.87 v. 7.01; p < 0.001) than atypical antipsy-
Antipsychotics vary 3 orders of magnitude in their chotic agents. The point here being that it is not the high
affinity (Kd or K,) for the D2 receptor. The data presented 5-HT2 affinity but the low D2 affinity that makes an
here demonstrate that the differences among antipsy- antipsychotic agent atypical.
chotics are mainly owing to the rate at which they come This finding poses an interesting challenge. Anti-
off the receptor. psychotic agents are used clinically in doses that are
Our study is limited to the 9 antipsychotics tested. inversely proportional to their affinity. This fact
This limitation was imposed by the number of radiola- remains true even in the case of the newer atypical anti-
belled antipsychotics available to us. Fortunately, we psychotic agents. For example, the relative in vitro
were able to access most of the labelled antipsychotics, affinities of haloperidol, risperidone, olanzapine and
and they spanned a range of affinity from 0.025 nmol/L clozapine for the D2 receptor are 1.5:3:17:150 nmol/L,
to 155 nmol/L and belonged to a range of different with haloperidol being most potent and clozapine the
chemical classes (phenothiazines, butyrophenones, sub- least.16 As predicted by these in vitro affinities, the clin-
stituted benzamides, dibenzazepines, dibenzoxaze- ical doses also share a similar relation haloperidol 2
pines), thus providing generalizability for these results. to 4 mg/d:risperidone 3 to 6 mg/d:olanzapine 10 to 20
A second limitation pertains to the extrapolation of mg/d:clozapine 250 to 450 mg/d. At first sight it may
kinetic results obtained in vitro to the in vivo situation. appear that giving 100 times more of a drug with a 100-
Our finding that the dilution estimates were no different times lower affinity should equate all things. Although
from the excess-raclopride estimates reinforces the fact giving a proportionally higher dose of a low-affinity
that the receptor homogenates and the drug behave antipsychotic agent may lead to equal occupancy at
under simple bimolecular assumptions in vitro.4 How- equilibrium (since equilibrium occupancy is based only
ever, in vivo the on-rate and the off-rate may be influ- on dose and affinity), the behaviour of these drugs
enced by a number of conditions. The access of the drug under dynamic circumstances will still be very differ-
to the receptor via blood flow or the passive-diffusion ent. This is where the differences in k,ff are crucial. We
limitations may exert additional constraints on the rate of illustrate the importance of k,f by considering some
association beyond that of the parameter k,n. Similarly, dynamic circumstances.
local conditions such as endogenous dopamine competi- When the concentration of a drug is increased it tends
tion, binding to spare receptors and rebinding after dis- toward a higher occupancy. However, the rate at which
sociation, as well as the modulating effect of other recep- the drugs move toward higher occupancy differs. The
tors could also alter the binding characteristics of drugs rate does not depend on affinity, but on the rate con-
to the D2 receptor.12114 Although it is likely that the precise stants kon and k,ff. The time to reach this new equilibrium
value of these parameters will differ in vivo, the general occupancy is inversely proportional to (kon X concentra-
principle identified herein should be applicable in ViVO.12 tion + k,ff)34 in situations where there is no drop in the
These findings have interesting implications for concentration of the drug due to the act of receptor-bind-
understanding the differences between antipsychotic ing. By substituting values from Table 1, one finds that
agents. One of the most comprehensive surveys of the 310 nmol/L of clozapine will reach a higher occupancy
receptor-binding properties of antipsychotics was by equilibrium 100 times faster than 4 nmol/L haloperidol.
Meltzer et al,15 who examined the binding of 37 atypical On the other hand, the rate at which a drug comes off the
or presumed atypical antipsychotics on dopamine D1 receptors, either when its concentration decreases or
and D2 as well as serotonin 5-HT2 receptors. This paper when there is competition from endogenous dopamine,
is usually cited in support of the serotonin-dopamine is determined by kff alone. From values in Table 1, one
hypothesis. But it is very important to note that Meltzer would expect 310 nmol/L of clozapine to come off the
et al reported no differences in the serotonin affinities of D2 receptor nearly a 100 times faster than 4 nmol/L
typical versus atypical antipsychotics (pKi values for 5- haloperidol, a finding that we have empirically demon-
HT2 affinity: 8.37 v. 8.36). They also found no difference strated in vitro before (unpublished data, 1999).
in D1 receptor binding either. The only major difference The higher dose of the agents with lower Kd, rather
between typical and atypical antipsychotics was in their than equating the dynamic differences, actually accen-
affinity for the D2 receptor. The typical antipsychotic tuates them. Since the drugs with a higher k, are given

Vol. 256
00. nO 2.2000 Journal m4i
.1 Psychiatry & Neuroaclence 165
C,, ,..=4i<iWs,.iX,vYiS
*....:ke. SV s>4- {S~~a-lv, 0s 0, d s- D--fN
X .,- .; Sz '§ t:' ..:

X -S,4< s^.X s<-.g

in much higher doses, they speed up the rate at which References

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and the EJLB Foundation (Canada). The financial con- 17. Kapur S, Zipursky R, Jones C, Shammi C, Remington G,
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tribution of Eli Lilly Canada to this project is thankfully pancy: a clinical PET study of quetiapine. Arch Gen Psychiatry
acknowledged. 1999; under review.


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