Psychopharmacology (1993) 112:285-292
Psychopharmacology
Seroquel: biochemical profile of a potential atypical antipsychotic
Charles F. Sailer*, Andre I. Salama
Department of Pharmacology, Zeneca Pharmaceuticals Group, Wilmington, DE 19897, USA
Received July 21, 1992/Final version February 16, 1993
Abstract. Seroquel and the atypical antipsychotic clozap-
ine were compared using a number of biochemical mea-
sures in rats which are indicative of potential antipsy-
chotic activity and possible extrapyramidal side effect li-
ability. Both in vitro and in vivo, these compounds are
low potency D-2 dopamine (DA) receptor antagonists
and are relatively more potent 5-HT 2 antagonists than
typical antipsychotic drugs. Seroquel also exhibited low
affinity for D-1 DA receptors in vitro, but D-1 receptor
occupancy was not detectable in vivo. Unlike clozapine,
Seroquel lacks appreciable activity at either D-1 DA or
muscarinic receptors. Following IP administration, both
compounds produce similar elevations in DA metabolite
concentrations. Following 1 month of daily administra-
tion, at doses which produce large increases in striatal
DA metabolite concentrations, both Seroquel and cloza-
pine fail, unlike typical antipsychotics, to increase the
number of striatal D-2 receptors, but do decrease the
number of 5-HT 2 receptors in frontal cortex. ICI 204,636
produces a short-lasting increase in plasma prolactin lev-
els, but these increases are much greater than those that
are produced by clozapine. One day after 3 weeks of daily
administration, tolerance, to the ability of Seroquel to
elevate DA metabolite and plasma PRL concentrations
is not observed. These biochemical observations are dis-
cussed with regard to the atypical profile of Seroquel in
behavioral and electrophysiological studies.
Key words: ICI 204,636 - Seroquel - Atypical antipsy-
chotic - Clozapine - Dopamine metabolism - 5-HT 2 re-
ceptor
The development of antipsychotic drugs has been a ma-
jor advance in the treatment of schizophrenia and other
behavioral disorders. Unfortunately, debilitating ex-
* Present address: Analytical BiologicalServicesInc., Cornell Busi-
ness Park, Wilmington, DE 19801, USA
Correspondence to: A.I. Salama
© Springer-Verlag 1993
trapyramidal motor side effects are associated with their
use. Acutely, these are manifest as dystonic reactions and
as Parkinsonian-like symptoms (Tarsy 1983). During
long-term treatments, a state of chronic motor dysfunc-
tion known as tardive dyskinesia can develop and persist
even after the discontinuation of antipsychotic medica-
tion (Tarsy 1983). Moreover, the side effects of antipsy-
chotic treatment can become so severe that they may
limit drug therapy.
Thus far, in the clinic, one antipsychotic drug, clozap-
ine, appears to be superior to other drugs with regard to
extrapyramidal side effect liability. Clozapine appears to
have very little propensity to produce these problems
(Gerlach et al. 1974; Matz et al. 1974; Shopsin et al. 1979;
Claghorn et al. 1987; Casey 1989). Primarily, because
clozapine does not produce extrapyramidal side effects, it
has been referred to as an atypical antipsychotic. Fur-
thermore, it has been reported that clozapine is effective
in patients who are not responsive to other antipsychotic
drugs (Kane et al. 1988). However, clozapine treatment is
associated with a high incidence of agranulocytosis,
which limits its usefulness (Griffith and Saameli 1977;
Anger et al. 1987; Lieberman et al. 1988). Therefore, con-
siderable research efforts have been directed at develop-
ing an atypical antipsychotic with a clozapine-like pro-
file.
Preclinical animal behavioral and electrophysiologi-
cal studies indicate that Seroquel 2-(2-[4-(dibenzol[b,f]
[1,4]thiazepin-ll-yl)piperazin-l-yl]ethoxy) ethanol) pos-
sesses the attributes of an atypical antipsychotic like
clozapine (Migler et al. 1993; Goldstein et al. 1993). As
with clozapine, Seroquel produces negligible catalepsy
and has a low propensity to produce dyskinesias in naive
and haloperidol sensitized Cebus monkey paradigms.
Responses in these models appear to predict the occur-
rence of extrapyramidal side effects in humans. In various
other behavioral tests, Seroquel is active as a DA antago-
nist, indicating potential antipsychotic activity (Migler et
al. 1993). Like all antipsychotic drugs that have been ex-
amined, Seroquel produces depolarization inactivation
of A10 mesolimbic DA-containing neurons. In addition,
286
like clozapine, but unlike typical antipsychotics, Seroquel
does not produce depolarization inactivation of A9 ni-
grostriatal DA-containing neurons (Goldstein et al.
1993). This type of profile is considered to be indicative of
an antipsychotic with a low propensity to produce ex-
trapyramidal side effects (White and Wang 1983; Chiodo
and Bunney 1985).
Since it is widely thought that the dopamine (DA)
receptor blocking properties of clozapine and other an-
tipsychotics m a y be largely responsible for their antipsy-
chotic properties and also their extrapyramidal side ef-
fects (Stevens 1973; Seeman and Lee 1975; Chang et al.
1986), we have compared the D A receptor blocking
properties of clozapine and Seroquel in both in vitro
binding studies and functional studies of D A receptor
blockade. In addition, activity of Seroquel at other brain
receptors was profiled because it has been speculated that
clozapine's atypical profile m a y be due to its actions at
non-dopaminergic receptors. In particular, we measured
the affinities and actions of Seroquel and clozapine on
5-HT 2 receptors, since we and others had speculated that
clozapine's actions at this serotonin receptor subtype
m a y contribute to an atypical antipsychotic profile (Altar
et al. 1986; Meltzer et al. 1989; Saller and Salama 1990).
However, this report is not intended to define or test a
particular hypothesis of the mechanism of action of
Seroquel or other potential atypical antipsychotic; but
rather, it is intended as a comparison of Seroquel with
clozapine on biochemical parameters which are widely
thought to be indicative of antipsychotic activity. Doses
of Seroquel and clozapine were selected that had similar
effectiveness in behavioral and electrophysiological stud-
ies (Migler et al. 1993; Goldstein et al. 1993).
Materials and methods
Animals. Male Sprague-Dawley rats, weighing 175-225 g at the
beginning of these studies, were used as subjects. The animals were
housed in a room which was maintained at 22°C and illuminated
with fluorescent lights (12 h on, 12 h off). Laboratory rat chow and
bottled tap water were available at all times.
Drug treatments. All drugs were dissolved in 0.1% (v/v) hydroxy-
propylmethylcellulose, 0.1. (v/v) Tween 80 in distilled water. The
injection volumes were 1 ml/kg for IP dosing. All drugs were admin-
istered within 2 h of the midpoint of the animals' light period.
Receptor binding assays. The binding of Seroquel and clozapine to
D-l, D-2, 5-HT, 5-HT2, ~zl- and ~z 2-adrenergic, muscarinic, and
benzodiazepine receptors was measured using minor modifications
of previously published methods (Greengrass et al. 1979; Leysen et
al. 1982; Hall et al. 1985; Howe and Yaksh 1986; Saller and Salama
1986a). B~ax and KD values for ligand binding to D-2 and 5-HT2
receptors were calculated using Scatchard analyses (Scatchard
1949).
In vivo receptor occupancy studies. The occupancy of D-l, D-2 and
5-HT2 receptors by Seroquel and clozapine was estimated by mea-
suring the ability of these drugs to prevent receptor inactivation by
N-ethoxycarbonyl-l,2-dihyroquinoline (EEDQ). Either Seroquel or
clozapine were administered at various times before EEDQ (10
mg/kg, IP) and the percent protection of D-l, D-2 and 5-HT2 by
these drugs was calculated as previously described (Saller et al.
1989).
Monoamine and monoamine metabolite assays. The tissue concentra-
tions of the monoamines DA, norepinephrine (NE) and 5-HT were
measured using an automated HPLC method using electrochemical
detection (Saller and Salama 1984). The tissue concentrations of the
major DA metabolites: 3,4-dihyroxyphenylalanine acid (DOPAC),
3-methoxytyramine (3-MT), and homovanilic acid (HVA), and the
5-HT metabolite 5-hydroxyindole acetic acid (5-HIAA) were also
measured using this assay. The animals used in these studies were
killed by microwave irradiation focused on their heads for 4 s to
rapidly inactivate tissue enzymes. A modified Litton microwave
oven was used for this purpose (General Medical Engineering, Pea-
body, MA, USA).
Since basal 3-MT concentration can fluctuate rapidly, 3-MT
accumulation, after inhibition of its catabolism by monoamine
oxide, was measured in these experiments. This was accomplished
by pretreating rats with pargyline (75 mg/kg, IP, a monoamine
oxidase inhibitor) and then Seroquel, clozapine, or their vehicle
were administered 30 min later (Saller and Salama 1986b). All ani-
mals were killed 45 min after the second injections and tissues were
stored at -80°C until analyses. 3-MT accumulation measured un-
der these conditions is a reliable index of DA release in response to
DA receptor blockade (Saller and Salama 1986b).
Plasma PRL assay. Animals were handled and acclimated to their
transfer cages, as was previously described, to minimize stress-in-
duced changes in plasma PRL concentrations (Saller and Salama
1986a). Plasma PRL concentrations were determined by radioim-
munoassay using antibody and standard (RP-2) supplied by the
National Institute of Arthritis, Metabolism, and Digestive Diseases.
Statistics. Comparisons between sample means were made using the
Newman-Keuls test or Student's t-test, as appropriate.
Results
In vitro receptor profile
In in vitro receptor binding assays, Seroquel appears to
be a low-potency D-2 antagonist with an ICs0 at D-2
binding sites that is about three times that of clozapine
(Table 1). Seroquel was also somewhat active at D-1 site
in vitro (Table 1). Unlike clozapine, Seroquel has virtual-
ly no activity at muscarinic binding sites (Table 1).It was
also inactive at benzodiazepine binding sites (Table 1). As
with clozapine, Seroquel exhibits affinity for 5-HT1Aand
5-HT 2 sites. Seroquel also possesses some affinity for ~ -
and ~2-adrenergic sites, but it was somewhat less active at
these sites than clozapine (Table 1).
D A and 5-HT2 receptor occupancy in vivo
Since the occupancy of D-2 and 5-HT 2 receptors by
Seroquel (see Introduction) m a y contribute to the atypi-
cal preclinical profile of Seroquel; the occupancy of D-2
and 5-HT2 receptors by Seroquel was estimated in vivo.
The relative in vivo receptor occupancy of 5-HT; and
D-2 receptors by Seroquel and clozapine was estimated
by measuring their ability to protect against EEDQ-in-
duced receptor inactivation. The time-course of 5-HT 2
and D-2 receptor occupancy, estimated in this manner, is
shown in Table 2. Both drugs provided significantly bet-
ter protection of 5-HT 2 than D-2 receptors. Likewise, the
D-2 receptor occupancy by either drug appeared to de-