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Home , Bromperidol, Carpipramine, Clocapramine, Clotiapine, Fluphenazine, Ketanserin

Kitakanto Med.J. 87

48( 2 ) : 87•`102, 1998

PROFILES OF THE AFFINITY OF

DRUGS FOR NEUROTRANSMITTER RECEPTORS

AND THEIR CLINICAL IMPLICATION

Kimie Yonemura, Kazuo Miyanaga, and Yukiteru Machiyama

Departmentof Neuropsychiatry,Gunma UniversitySchool of Medicine

Abstract : The binding affinities of 12 different neurotransmitter receptors were measured using a

radio-labeled assay.

The profiles of the pharmacological affinities of 20 antipsychotic were assessed. Based on the

Ki values for the D2 receptor, 5HT2 receptor, and ƒ¿1 receptor, the antipsychotic drugs were classified into

five groups (i.e., three anti-DA activity predominant groups and two anti-5HT activity predominant

groups). A theoretical basis for choice in clinical settings is also proposed. We recommend that the

groups of the drugs having predominantly anti-DA activity be used in the treatment of and and that the drugs in the anti-5HT activity predominant group be used to treat hypobulia. If

it is necessary to administer two or more of these drugs together, we propose that they should be drugs

with different profiles. , side effects of antipsychotic drugs, were interpreted in

terms of interaction among the anti-D, activity, anti-5HT2 activity, and anti-Ach activity.

Key words : Antipsychotic drugs, Anti-DA action, Anti-5HT action, Anti- action,

Extrapyramidal symptoms.

(Kitakanto Med.J. 48 (2) : 87•`102, 1998)

number of reports on the affinity of antipsychotic INTRODUCTION agents for receptors have been published both in Japan A variety of antipsychotic agents have been devel- and other countrieso. The reports, however, have often

oped for clinical use since 1952, when the effectiveness dealt with drugs that are seldom used or not used at all of in treating was first at present in Japan. demonstrated. However, selection of antipsychotic The present study was undertaken to assess the

drugs in individual cases has often been empirical, affinity for receptors of clinically popular antipsy- without any definite theoretical or pharmacological chotic drugs, and to obtain comprehensive profiles of guidelines. This is corroborated by the tendency for their pharmacologic actions, with the ultimate goal of psychiatrists in different countries to prescribe different providing a theoretical basis for selecting drugs in drugs for the same mental symptom and there are also individual clinical cases. differences between university hospitals and other MATERIALS AND METHODS hospitals within Japan.

As a result of recent advances in pharmacological Nineteen antipsychotic drugs on the market in

research on neurotransmitter receptors in the brain, the Japan and one that is currently being developed were mechanism of action of antipsychotic drugs has been investigated by radiolabeled receptor assay1•`7) in

increasingly elucidated, and it now seems possible to regard to their affinity for the receptors of 12 different argue for the establishment of theoretical foundations neurotransmitters.

for the selection of drugs to treat mental symptoms. A Materials and methods ( [3H] ligands, membrane

Received : December 22, 1997 Accepted : January 21, 1998 Address : KIMIE YONEMURA Department of Neuropsychiatry Gunma University School of Medicine 3-39-22 Showamachi, Maebashi, Gunma, 371-8511, Japan 88

Yonemura, Miyanaga, Machiyama

Table 1. Materials and methods

preparation, buffers, incubation conditions and the 50mM Tris/HCl (120mM NaCl, 5mM MgC12, 5mM drugs to test for nonspecific binding) are summarized KCl, 1.5mM CaC12, 5mM EDTA : pH7.4) and in 25

in Table 1. volumes of 50mM Tris/HCl (120mM NaCl, 5mM KCl,

5mM MgC12, 1mM EDTA : pH7.4), respectively.

I . Membrane preparation C. lA (5HT1A) receptor

A. 1 (D1) receptor and dopamine 2 (D2) Hippocampus of the male Wistar rat (200-250g)

receptor was used. The method of homogenation was the same

Striatum of male Wistar rat (200-250g) was procedure described in the paragraph of dopamine 1 homogenized in 30 volumes of 50mM Tris/HC1 (pH receptor and dopamine 2 receptor.

7.5) with an ultrasonic homogenizer (Nihonseiki Fac- D. Serotonin 3 (5HT3) receptor tory). The homogenate was centrifuged at 50,000 •~ g Cerebral cortex of male Wistar rat (200-250g) was for 20 min and the pellet was resuspended in 30 vol- used. The method of homogenation was the same umes of 50mM Tris/HC1 (pH7.5), and the same proce- procedure described in the paragraph of dopamine 1 dure was repeated two more times. The resulting pellet receptor and dopamine 2 receptor, except for the kind was then suspended in 3 volumes of the same buffer. In of buffer (50mM HEPES : pH7.5). the binding assay, the suspension was diluted to an E. Serotonin 2 (5HT2) receptor, ƒ¿1 (ƒ¿1) appropriate concentration and used as the crude mem- receptor, adrenaline ƒ¿2 (ƒ¿2) receptor, and branes fraction for the binding assay. (Ach) receptor

B. Dopamine 3 (D3) receptor and Dopamine 4 (D4) Cerebral cortex of male Wistar rat (200-250g) was receptor used. The method of homogenation was the same The membranes from Chinese hamster ovary procedure described in the paragraph of dopamine 1

(CHO) cells expressing the cloned human and dopamine 2 receptor. D3 receptor and D4 receptor were used. These materi- F. 1 (H1) receptor als were obtained from the Yamanouchi Pharmaceuti- Brain stem of male Wistar rat (200-250g) was used. cal Co.,Ltd. and DuPont, respectively. They were The method of homogenation was the same procedure stored frozen at -70•Ž until used. Before the binding described in the paragraph of dopamine 1 receptor and study, the membranes were diluted in 7.5 volumes of dopamine 2 receptor. 89

The affinity of antipsychotic drugs for receptors

G. Sigma (ƒÐ) receptor solution (DuPont-NEN), 100ƒÊl of displac-

Whole brain of male Wistar rat (200-250g) was ing drugs (antipsychotic drugs), 700ƒÊl of 50mM Tris/

used. The method of homogenation was the same HC1 (120mM NaCl, 5mM KCl, 1mM MgC12, 1mM

procedure described in the paragraph of dopamine 1 CaC12 ; pH7.5), and 100ƒÊl of resuspended homogenate receptor and dopamine 2 receptor. (0.1-0.2mg protein/tube). Incubation conditions were 37°C for 30min. Nonspecific binding was determined

All suspensions were stored frozen at -70•Ž. Before in the presence of 10ƒÊM (SIGMA). the 5HT1, receptor and ƒÐ receptor binding assays, the (3) D3 receptor suspension was incubated for 20 min at 37•Ž and 60 The receptor binding assay was performed accord-

min at 37•Ž, respectively. The protein concentration ing to the method of Tada et al11).

was measured by the method of Lowry, with bovine The binding assay consisted of 100ƒÊl of 4nM [3H]

serum albumin as the protein standard. YM-09151-2 () solution (DuPont-NEN),

100ƒÊl of displacing drugs (antipsychotic drugs),

II. Antipsychotic drugs 1700ƒÊl of 50mM Tris/HCl (120mM NaC1, 5mM

The antipsychotic drugs used in this study and their MgC12, 5mM KCl, 1.5mM CaC12, 5mM EDTA ;

sources were as follows : Chlorpromazine HCl, pH7.4), and 100ƒÊl of membrane suspension (8/2g

maleate, propericiazine, perphen- prot./tube). Incubation conditions were 25°C for 30 azine maleate, maleate, , min. Nonspecific binding was determined in the

, , HCl, cloca- presence of 10ƒÊM Quinpirol (RBI). pramine HCl HCland , from Yoshitomi Phar- (4) D4 receptor maceutical Ind., Ltd. ; HCl and oxyper- The receptor binding assay was performed accord- tine, from Sandoz Pharmaceuticals Ltd. ; , ing to the method of Van Tol et al.12). , and sulpiride, from Fujisawa Pharmaceuti- The binding assay consisted of 100ƒÊl of 50nM [3H] cal Co.,Ltd. ; , from Daiichi Pharmaceuti- spiperone solution (DuPont-NEN), 100ƒÊl of displac- cal Co.,Ltd. ; HCl, from Dainippon Phar- ing drugs (antipsychotic drugs), 700ƒÊl of 50mM Tris/

maceutical Co.,Ltd. ; nemonapride, from Yamanouchi HCl (120mM NaCl, 5mM KCl, 5mM MgC12, 1mM

Pharmaceutical Co.,Ltd. ; and SM-9018, from EDTA ; pH7.4), and 100ƒÊl of membrane suspension

Sumitomo Pharmaceutical Co.,Ltd.. (22ƒÊl prot./tube). Incubation conditions were 25°C Most of the drugs used as displacing drugs were for 60 min. Nonspecific binding was determined in the

dissolved in distilled , but, propericiazine, presence of 100ƒÊM nemonapride (Yamanouchi Phar- clotiapine, zotepine, haloperidol, timiperone, maceutical Co.,Ltd.).

bromperidol, and pimozide were dissolved in 0.1% 13, 5HT receptor

. (1) 5HT1, receptor The receptor binding assay was performed accord-

III. Radio Receptor Assays ing to the method of Peroutka et al.'3).

A. DA receptor The binding assay consisted of 100ƒÊl of 6nM [3H]

(1) D1 receptor 8-OH-DPAT solution (DuPont-NEN), 100ƒÊl of dis-

The receptor binding assay was performed accord- placing drugs (antipsychotic drugs), 100ƒÊl of 0.1% ing to the method of Billard et al.8). ascorbic acid, 100ƒÊl of 10nM (SIGMA),

The binding assay consisted of 100ƒÊl of 2nM [3H] 500ƒÊl of 50mM Tris/Hl (pH7.5), and 100ƒÊl of

SCH23390 solution (DuPont-NEN), 100ƒÊl of displac- resuspended homogenate (0.10-0.15mg prot./tube).

ing drugs (antipsychotic drugs), 700ƒÊl of 50mM Tris/ Incubation conditions were 30•Ž for 20min. Non-

HC1 (120mM NaCl, 5mM KCl, 1mM MgC12, 1mM specific binding was determined in the presence of

CaC12 ; pH7.5), and 100ƒÊl of resuspended homogenate 10ƒÊM serotonin (SIGMA).

(0.1mg protein/tube). Incubation conditions were (2) 5HT2 receptor 37°C for 30 min. Nonspecific binding was determined The receptor binding assay was performed accord-

in the presence of 10ƒÊM fluphenazine (Yoshitomi ing to the method of Leysen et al14).

Pharmaceutical Ind. Ltd.). The binding assay consisted of 100ƒÊl of 10nM [3H]

(2) D2 receptor solution (DuPont-NEN), 100ƒÊl of displac- The receptor binding assay was performed accord- ing drugs (antipsychotic drugs), 700ƒÊl of 50mM Tris/

ing to the method of Creese et al.9). and Seeman et HCl (pH7.5), and 100ƒÊl of resuspended homogenate al.10). (0.1-0.2mg prot./tube). Incubation conditions were The binding assay consisted of 100ƒÊl of 5nM [3H] 37•Ž for 20min. Nonspecific binding was determined 90

Yonemura, Miyanaga, Machiyama

in the presence of 1ƒÊM ketanserin (RBI). 25°C for 60min. Nonspecific binding was determined

(3) 5HT3 receptor in the presence of 500pM (Yoshitomi

The receptor binding assay was performed accord- Pharmaceutical Ind. Ltd.).

ing to the method of Nelson et a1.15) and Sakamori et F.

al.16). The receptor binding assay was performed accord-

The binding assay consisted of 100ƒÊl of 26nM [3H] ing to the method of Zukin et al.20 and Tam et al.22).

BRL-43694 solution (DuPont-NEN), 100ƒÊl of dis- The binding assay consisted of 100ƒÊl of 20nM [31-I]

placing drugs (antipsychotic drugs), 600ƒÊl of 50mM (4-) SKF10047 solution (DuPont-NEN), 100ƒÊl of HEPES (pH7.5), and 200ƒÊl of resuspended homo- displacing drugs (antipsychotic drugs), 700ƒÊl of 50mM

genate (0.3mg prot./tube). Incubation conditions were Tris/HCI (pH7.5), and 100ƒÊl of resuspended 25•Ž for 40min. Nonspecific binding was determined homogenate (0.2-0.3mg prot./tube). Incubation condi-

in the presence of 10ƒÊM (Smith-Kline tions were 4°C for 60min. Nonspecific binding was

Beecham Consumer). determined in the presence of 30ƒÊM (-) SKF 10047

C. a adrenaline (a-Ad) receptor (RBI). (1) a, receptor

The receptor binding assay was performed accord- After incubation, 5ml of ice-cold buffer was added

ing to the method of Peroutka et al.'7). to the assay mixtures. The mixtures were then rapidly

The binding assay consisted of 200ƒÊl of 3nM [3H] filtered under a vacuum through Whatman GB/F

solution (Dupont-NEN), 100ƒÊl of displacing filters. After washing with 2 •~ 5ml of ice-cold buffer, drugs (antipsychotic drugs), 100,u1 of 0.01% ascorbic the filter was dried by heating at 90•Ž for 2h. Radio-

acid, 500ƒÊl of 50mM Tris/HCI (pH7.5), and 100ƒÊl of activity was measured with a liquid scintillation

resuspended homogenate (0.15mg prot./tube). Incuba- counter (Aloka LSC-700) in 5 ml of Aquasol (AQUA

tion conditions were 25•Ž for 30min. Nonspecific SOL-2 ; DuPont). In the D4 receptor and ƒÂ receptor

binding was determined in the presence of 10,uM experiments, the Whatman GB/F filter was soaked in

prazosin (SIGMA). 0.5% polyethyleneimine (SIGMA) for 60min.

(2) cr, receptor Saturation experiments were performed with 5 to 8

The receptor binding assay was performed accord- [3H] concentrations. Data are reported as the ing to the method of U'Prichard et al.'8). mean values of triplicate assays performed in each

The binding assay consisted of 100ƒÊl of 1nM [3f1] experiment. solution (DuPont-NEN), 100/ƒÊl of displac-

ing drugs (antipsychotic drugs), 700,ƒÊl of 50 mM Tris/ Iv. The analysis of results of the binding assays HC1 (pH7.5), and 100ƒÊl of resuspended homogenate The dissociation constant (Kd) and maximal num-

(0.2mg prot./tube). Incubation conditions were 25•Ž ber of binding sites (Bmax) were determined by Scat- for 60min. Nonspecific binding was determined in the chard plots of data from the saturation experiments for presence of 1004 clonidine (SIGMA). each receptor. The affinity constant (Ki) of each D. Ach receptor antipsychotic drug was obtained from the inhibition The receptor binding assay was performed accord- curve of the displacement experiment data, i.e, Ki ing to the method of Yamamura et aI.19). values were calculated as follows : Ki = IC50/(1+ C/ The binding assay consisted of 100ƒÊl of 0.7nM [3H] Kd), where IC50 is the concentration that 50% inhibits

QNB solution (DuPont-NEN), 100ƒÊl of displacing [3H] ligand binding ; Kd is dissociation constant ; drugs (antipsychotic drugs), 700ƒÊl of 50mM Tris/HCI and C is the concentration of [3H] ligand.

(pH7.5), and 100/ƒÊl of resuspended homogenate (0.2mg RESULTS prot./tube). Incubation conditions were 25•Ž for 60min. Nonspecific binding was determined in the Fig.l shows the results of the D3 binding assay as presence of 0.5ƒÊM QNB (SIGMA). example. Fig.1(a) shows the results of the saturation E. Histamine 1 receptor experiment. Fig.1(b) is the Scatchard plot and shows The receptor binding assay was performed accord- the Kd value and Bmax. Fig.1(c) shows the displace- ing to the method of Hill et a1.19). ment curve of haloperidol for the D3 receptor and the The binding assay consisted of 100,ƒÊl of 32nM [3H] IC50. The experiments showed sufficient repro- pyrilamine solution (DuPont-NEN), 100ƒÊl of displac- ducibility. Similar plots were obtained for the other ing drugs (antipsychotic drugs), 700ƒÊl of 50mM Tris/ receptors and the other antipsychotic drugs. All Ki HC1 (pH7.5), and 100ƒÊl of resuspended homogenate values obtained in this study are summarized in Table

(0.25-0.30mg prot./tube). Incubation conditions were 2. 91

The affinity of antipsychotic drugs for receptors

Fig. 1 Analysis of 3H-YM-09151-2 binding to D3 receptors a Direct plot of 3H-YM-09151-2 binding to D3 receptors b Scatchard plot of 3H-YM-09151-2 binding to D3 receptors

●,■ two separate experiments, each performed in tripli- Kd and Bmax were obtained from this plot.

cate.

c Displacement curve of haloperidol for D3 receptors

The IC50 of haloperidol could be determined from this plot.

The Ki value of haloperidol is 15.2•}4.1nM (3 determinations).

I . Ki value of each test drug of 100nM) was shown by thioridazine, timiperone,

A lower Ki value indicates greater ability of a drug haloperidol, and bromperidol. Low affinity (Ki over to bind to receptors and to block the binding of 1ƒÊM) was shown by pimozide, sulpiride, sultopride, radioactive ligands to the receptors. Thus, higher nemonapride, and SM-9018. All affinity for a receptor is associated with a more potent except thioridazine were found to have high affinity pharmacologic action. for D, receptors. In this report, the affinity of drugs for receptors is (2) D2 receptors rated on a four-point scale : high affinity (drugs with a High affinity for D2 receptors was found for timi-

Ki value on the order of 1nM or less), moderate perone, fluphenazine, nemonapride, , affinity (Ki on the order of lOnM), relatively low bromperidol, primozide, mosapramine, SM-9018,

affinity (Ki on the order of 100nM) and low affinity haloperidol, , levomepromazine, and

(Ki over 1ƒÊM). zotepine. Moderate affinity for D2 receptors was A. DA receptors shown by chlorpromazine, carpipramine, sulpiride, (1) D1 receptors sultopride, , propericiazine, and clotiapine. The affinity of the following drugs for D1 receptors Relatively low affinity was shown by thioridazine. (i.e., the ability to block D1 receptors) was high (Ki on (3) D3 receptors the order of 1nM) : fluphenazine, perphenazine, High affinity for D3 receptors was shown by levomepromazine, and chlorpromazine. The Ki of timiperone, pimozide, nemonapride, SM-9018, flu-

these drugs for D, receptors ranged between 2.5nM and phenazine, mosapramine, perphenazine, clocapramine, 6.3nM. Moderate affinity (Ki on the order of lOnM) and chlorpromazine. Moderate affinity was shown by was recorded for propericiazine, clocapramine, zotepine, haloperidol, levomepromazine, bromperidol,

clotiapine, zotepine, carpipramine, oxypertine, and propericiazine, sultopride, thioridazine, clotiapine, mosapramine. Relatively low affinity (Ki on the order and carpipramine. Relatively low affinity was shown 92

Yonemura, Miyanaga, Machiyama

Table 2. Ki values of

Ki values were calculated by using the formula : IC50/(1.+C/Kd), where IC50 is the concentration of the drug that half maximaly displaces the 3H-ligand, C is the concentration of 3H-ligand, and Kd is its dissociation constant. The data printed in boldface could not be found in any report except ours. by sulpiride and oxypertine. B . 5HT receptors (4) D4 receptors (1) 5HT1A receptors High affinity for D4 receptors was shown by As a whole affinity for 5HT1A receptors tended to timiperone, haloperidol, bromperidol, nemonapride, be low. High affinity was shown by SM-9018. None and clotiapine. Moderate affinity was shown by SM of the antipsychotic agents currently on the market -9018 , clocapramine, pimozide, zotepine, thioridazine, showed high affinity for this receptor. Moderate chlorpromazine, levomepromazine, and properici- affinity was shown by nemonapride. Relatively low azine. Relatively low affinity was shown by masa- affinity was shown by zotepine, oxypertine, pimozide, pramine, fluphenazine, carpiramine, perphenazine, and timiperone, etc. All except nemonapride oxypertine. Low affinity was shown by sulpiride and had low affinity (Ki over 1ƒÊM). sultopride, i.e., by all benzamides tested except (2) 5HT2 receptors nemonapride. As a whole affinity for 5HT2 receptors tended to be high. Levomepromazine, SM-9018, clocapramine, carpi- 93

The affinity of antipsychotic drugs for receptors

pramine, perphenazine, propericiazine, chlorprom- F. Sigma receptors azine, timiperone, mosapramine, fluphenazine, High affinity for a receptors was shown by haloperi- clotiapine, zotepine, thioridazine, and pimozide had dol, perphenazine, fluphenazine, clocapramine, chlor- high affinity (Ki on the order of 10-2nM with the first , and levomepromazine. Moderate affinity two drugs). Moderate affinity was shown by oxyper- was shown by carpipramine, timiperone, clotiapine,

tine, haloperidol, and bromperidol. Low affinity was zotepine, pimozide, bromperidol, thioridazine, properi-

shown by benzamides. ciazine, and oxypertine. Low affinity was shown by

(3) 5HT3 receptors mosapramine, SM-9018, and the benzamides. Most test drugs had a Ki value over 100nM, that is,

low affinity for 5HT3 receptors. Relatively high affin- II. Ki-based classification of antipsychotic drugs

ity for this receptor was shown by perphenazine According to the report by Otsuki et al.23), on the

(470nM), chlorpromazine (600nM), and levomeprom- relationship between clinical symptoms and neurotrans- azine (800nM). mitters (DA, 5HT and Ad), the pharmacologic actions

C . Ad receptors of antipsychotic agents are primarily explained by and -D (1) ƒ¿1 receptors 2 activity, anti-5HT2 activity and anti-ƒ¿1 activity5). High affinity for ƒ¿1, receptors was shown by thiorid- Based on their report, we attempted to classify antipsy-

azine, SM-9018, levomepromazine, chlorpromazine, chotic agents. First, the drugs were classified accord-

timiperone, zotepine, propericiazine, bromperidol, and ing to the strength of anti-5HT2 activity, and anti-D2

oxypertine. Moderate affinity was shown by perphen- activity, and then subclassified according to the

azine, haloperidol, clotiapine, pimozide, mosa- strength of anti-ƒ¿1 activity. This yielded five groups,

pramine, fluphenazine, and carpipramine. Among the i.e., three DA receptor blockade dominant groups and benzamides, nemonapride had a Ki of 620nM for this two 5HT receptor blockade dominant groups, as

receptor, but the other drugs in the family had low shown in Table 3.

affinity (Ki over 1ƒÊM). A. DA receptor blockade dominant groups

(2) ƒ¿2 receptors (1) Group A

High affinity was shown by clocapramine. Moder- The anti-D2 activity is the major activity and there

ate affinity was shown by carpipramine, fluphenazine, is hardly any anti-5HT2 activity (anti-D2 activity/anti -5HT and perphenazine. Relatively low affinity was shown 2 activity •†100). Sulpiride, which has no anti -a by SM-9018, chlorpromazine, zotepine, thioridazine, , activity, and nemonapride, which has an anti-a,

pimozide, levomepromazine, propericiazine, mosa- activity, belong to this group.

pramine, and nemonapride. The other drugs showed (2) Group B low affinity. The anti-D2 activity is the major activity, and a

D. Ach receptors weak anti-5HT2 activity is also observed (100> anti -D High affinity was shown by chlorpromazine and 2 activity/anti-5HT2 activity•† 10). Haloperidol levomepromazine. Moderate affinity was shown by and bromperidol, members of the fam-

oxypertine, clotiapine, thioridazine, zotepine, cloca- ily, belong to this group.

pramine, perphenazine, and timiperone. Relatively (3) Group C low affinity was shown by fluphenazine, mosapramine, The anti-D2 activity is slightly stronger than the

bromperidol, haloperidol, propericiazine, and pimo- anti-5HT2 activity (10> anti-D, activity/anti-5HT2

zide. Low affinity was shown by carpiramine, sulpi- activity•†1). Fluphenazine, timiperone, and pimozide

ride, sultopride, nemonapride, and SM-9018. belong to this group.

E Histamine receptors B. 5HT receptor blockade dominant groups

The Ki for H1 receptors was on the order of lOnM (1) Group D or higher with all of the drugs tested. Moderate The anti-5HT2 activity is the major activity (anti -5HT affinity for H1 receptors was shown by mosapramine, 2 activity/anti-D2 activity•†10). This group can chlorpromazine, perphenazine, and propericiazine. be divided into three subgroups : (1) drugs with little

Relatively low affinity was shown by pimozide, thior- anti-a1 activity (carpipramine), (2) drugs with anti-a1

idazine, clotiapine, timiperone, fluphenazine, levome- activity comparable to their anti-D2 activity (chlor-

promazine, SM-9018, zotepine, and clocapramine. promazine, levomepromazine, clotiapine, peroperici- Low affinity was shown by haloperidol, bromperidol, azine, perphenazine, and SM-9018), and (3) drugs with

carpipramine, oxypertine, nemonapride, sulpiride, and strong anti-ƒ¿1, activity (thioridazine).

sultopride. (2) Group E

The anti-5HT2 activity is slightly stronger than the 94

Yonemura, Miyanaga, Machiyama

Table 3. Classification of antipsychotics

Based on their Ki values for the D2 receptor, 5HT2 receptor, and ƒ¿1 receptor , the antipsychotic drugs wereclassified into five groups Anti-D2 activity dominant drugs were divided three groups. Group A:This group contains drugs that meet the condition: (1/KiD2)/(1/Ki5HT2)≧100 Group B:This group contains drugs that meet the condition: 100>(1/KiD2)/(1/Ki5HT2)≧10 Group C:This group contains drugs that meet the condition: 10>(1/KiD2)/(1/Ki5HT2)≧1 Anti-5HT2 activity dominant drugs were divided two groups. Group D:This group contains drugs that meet the condition: (1/Ki5HT2)/(1/KiD2)≧10 Group E:This group contains drugs that meet the condition: 10>(1/Ki5HT2)/(1/KiD2)≧1 We recommend the following guidelines for selecting drugs ; When the patient has severe hallucinations and/or delusions, drugs belonging to anti-D2 activity dominant groups should be used . When the patient shows negative symptoms, drugs belonging to anti-5HT2 activity dominant groups should be used .

anti-D2 activity (10> anti-5HT2 activity/anti-D2 shown that simultaneous stimulation of D1 and D2 activity •† 1). This group can be divided into two receptors results in stereotyped behavior25'26). Oral subgroups : (1) drugs with little anti-ƒ¿1 activity (mosa- has also been reported when D1 receptors pramine and clocapramine) and (2) drugs with anti-a1 were blocked after blocking D2 receptors27). These activity comparable to their anti-D2 activity (zotepine findings suggest that blockade of D1 receptors is also and oxypertine). involved in antipsychotic actions. In the present study, high affinity for D1 receptors DISCUSSION (Ki on the order of 1nM) was shown by pheno- I . Affinity of antipsychotic agents thiazines such as fluphenazine, perphenazine, levome- A. DA receptors promazine, and chlorpromazine. The affinity of butyro- In 1976, Seeman et al.24)showed that the therapeu- phenones for D1 receptors was lower (Ki on the order doses of antipsychotic agents were inversely cor- of 100nM). Data concerning anti-D1 action have been related with their ability to bind to DA receptors. reported by Hyttel et al.28)and Kinoshita29). The IC5o Since then, blockade of DA receptors has been consid- reported for antipsychotic agents by Hyttel et al. was ered a major mechanism of antipsychotic actions. about 10 times lower than that obtained in the present As a result of recent advances in pharmacology and study. This discrepancy is probably due to the differ- molecular biology studies, it has been found that DA ence in ligands used in the two studies. Consistent receptors can be divided into five subtypes. These five with previous reports, the anti-D, receptor activity of subtypes are grouped into two families on the basis of phenothiazines tended to be higher than that of butyro- their pharmacologic profiles : the D1 family (D1 and phenones in the present study. No reports prior to the D5) and the D2 family (D2, D3 and D4). The present present study have dealt with the affinity of levome- study dealt with D1, D2, D3 and D4. promazine, propericiazine, clothiapine, zotepine, (1) D1 family timiperone, carpipramine, oxypertine, or sultopride for D1 receptors are distributed in the corpus striatum , D1 receptors. the , the limbic system, and the ventral (2) D2 family tegmental area. Behavioral pharmacology studies have The same as D1 receptors, D2 receptors are dis- 95

The affinity of antipsychotic drugs for receptors

tributed in the corpus striatum, the substantia nigra, B 5HT receptors the limbic system, the ventral tegmental area. Blockade 5HT has been reported to be involved in mood of D2 receptors is a pharmacologically important disorders and symptoms of schizophrenia such as action that suppresses hallucinations and delusions. , , obsession, and aggressiveness34). Consistent with previous reports, were At present, 7 families (14 subtypes) of 5HT receptor are found to have higher affinity for D2 receptors than known. The present study dealt with 5HT1A, 5HT2, phenothiazines in the present study. A number of and 5HT3 receptors. reports on anti-D, receptor activity have been pub- 5HT1A receptors are distributed in the limbic sys- lished, but the data for the potency of this activity tern, the raphe nuclei and the hippocampus. They are differ by more than 10 fold among the different reports. involved in body temperature and blood pressure Thus, the exact potency of this activity is unknown. regulation, eating behavior, anxiety, and aggressive- The potency of this activity obtained in the present ness35). In the present study, the affinity of all antipsy- study was within the range of this parameter reported chotic agents for 5HT1A receptors was on the 100nM in the past. No reports prior to the present study have order. Affinity for 5HT1A receptors was low with all dealt with the affinity of propericiazine, or clothiapine agents except SM-9018 and nemonapride. Nishizaki36) for D7 receptors. and Zolan et al.37) have reported the affinity of anti- D3 receptors are mainly distributed in the limbic psychotic agents for this type of receptor. The data system. They serve as the autoreceptors of DA neu- obtained in the present study were similar to the data rons") and are involved in mental functions such as in their report. No reports prior to the present study cognition and emotion.30) The anti-D3 receptor activ- have dealt with the affinity of levomepromazine, ity of chlorpromazine, thioridazine, and clotiapine is propericiazine, perphenazine, fluphenazine, clotiapine, higher than their anti-D2 receptor activity. Anti-D3 timiperone, pimozide, carpipramine,clocapramine, receptor activity has also been reported by Tada et oxpertine or sultopride for 5HT1A receptors. Tando- al11). and Sokoloff et al.30. The data obtained in the spirone has recently been used clinically as a nonbenzo- present study was similar to their data. No reports diazepine . This drug is said to serve as a prior to the present study have dealt with the affinity of 5HT1A and to suppress 5HT neurons via the levomepromazine, propericiazine, perphenazine, autoreceptor 5HT,A38,39).In the present study, the Ki clotiapine, zotepine, timiperone, carpipramine,oxy- for this receptor was lower (i.e., the affinity for this pertine, or sultopride for D3 receptors. receptor was greater) with SM-9018 and nemonapride D4 receptors are distributed in the cerebral cortex than with (Ki = 92nM5)). SM-9018 has and the limbic system. has been shown to not yet been introduced clinically and no detailed data be useful in the treatment of chronic schizophrenia on this drug is available. Nemonapride is known to characterized by negative symptoms (e.g., avolition, have antianxiety activity") and seems to act as a 5HT1A affective flattening, and social withdrawal) and agonist, the same as tandospirone. treatment-resistant schizophrenia, and to block D4 5HT2 receptors are distributed widely in the cere- receptors12). On the basis of such findings, a relation- bral cortex and the basal ganglia. They are involved in ship between anti-D4 receptor activity and successful stereotypic behaivior, anxiety, depression, obsession, treatment of negative symptoms was hypothesized. In and aggressiveness35). The affinity for this receptor was recent years, however, it has been reported that only a high with levomepromazine, clocapramine, carpi- small number of D4 receptors are present in the pramine, perphenazine and propericiazine. All of brain32'33). Thus, the validity of the this hypothesis has these drugs except levomepramazine are often used to not yet been confirmed. In the present study, butyro- treat patients with negative symptoms or avolition, phenones and SM-9018 (an providing clinical evidence of the importance of 5TH2 agent) were found to have relatively high anti-D4 recep-tor blockade in treating these symptoms. receptor activity. The data obtained in the present Hamon41) and Harada42) reported that antipsychotic study concerning the potency of anti-D, receptor drugs have affinity for 5HT2 receptors. The data activity of antipsychotic agents was similar to that obtained in the present study on the affinity of antipsy- reported by Van Tol et al12). No reports prior to the chotic drugs for this receptor is similar to theirs. No present study have dealt with the affinity of levome- reports prior to the present study have dealt with the promazine, propericiazine, perphenazine, clotiapine, affinity o f lev ome timiperone, carpipramine, oxypertine, or sultopride for promazine, propericiazine, clotiapine, timperone, D4 receptors. carpipramine, or sultopride for 5HT2 receptors. 5HT3 receptors are distributed in the cerebral cor- 96

Yonemura, Miyanaga, Machiyama

tex, the hippocampus and the amygdala. They are Prior to the present study, Setoguchi et al.47) and reported to be involved in anxiety, memory, cognition, Hasegawa et al48). reported on the affinity of drugs for

vomiting, and promotion of the release of DA and α2 receptors. Our data is similar to that reported by

GABA. More recently, it has been reported that 5HT3 Setoguchi et al., but not similar to that reported by

antagonists manifest antianxiety activity35). In the Hasegawa et al. The Ki value reported by Hasegawa et

present study, the Ki was between 100nM and licM or al. was several times higher than that obtained in the higher, indicating low affinity for 5HT3 receptors. present study and this discrepancy is unclear. No Phenothiazines showed relatively high affinity for this reports prior to the present study have dealt with the

receptor, suggesting that 5HT3 receptors are partially affinity of clotiapine, zotepine, timiperone, or sulto- related to the actions of drugs. A few reports pride for ƒ¿2, receptors. on anti-5HT3 receptor activity have been published, D . Muscarinic but the data for the potency of this activity differ by Ach receptors are distributed in the cerebral cortex, more than 3-4 fold among the different reports. This the corpus striatum, and the lateral nucleus accumbens. discrepancy is probably due to the difference in ligands Blockade of Ach receptors is associated with auto- and tissues used in these studies43). No reports prior to nomic nervous system symptoms (thirst, , the present study have dealt with the affinity of thio- anuresis, intraocular hypertension, etc.)49) and with ridazine, perphenazine, clotiapine, timperone, pimo- reduction of cognitive function. At present, acetyl- zide, carpipramine,oxypertine, sulpiride or sultopride drugs are being developed for use in treat- for 5HT3 receptors. ing memory disturbances in demented patients50). This C. Ad receptors means that the Ach receptor blocking action of anti- Adrenaline (Ad) serves as a neurotransmitter of the psychotic agents can induce cognitive disturbances as sympathetic nervous system and the adrenergic neurons adverse reactions. Blockade of Ach receptors in the of the central nervous system. Central adrenergic corpus striatum suppresses the emergence of extrapy- nerves, which can be divided into locus coeruleus ramidal symptoms induced by blockade of D2 recep- system and lateral tegmental system, are involved in tors. The results of the present study suggest that level of consciousness, anxiety, memory, and learn- butyrophenones have lower anti-Ach receptor activity ing44,45). Ad receptors can be classified into alpha and and are more likely to induce extrapyramidal symp- beta families. The former excites the nervous system, toms than phenothiazines, which is consistent with our while the latter inhibits it. Two subtypes of the alpha clinical experience. family were investigated in the present study. Data reported in the past concerning anti-Ach α1 receptorsaredistributedinthethalamus,cere一 receptor activity have varied greatly among reports, bral cortex, vagal nerve nuclei, and raphe nuclei. and thus detailed analysis is difficult. No reports prior Otsuki et al23). reported that blockade of ƒ¿1 receptors to the present study have dealt with the affinity of resulted in sedation, reduction of anxiety, and reduc- propericiazine, clotiapine, timiperone, carpipramine, tion of the level of consciousness or attention. In the or sultopride for Ach receptors.

present study, anti-ƒ¿1, activity was found to be high E . Histamine receptors with thioridazine, chlorpromazine, and levome- Histamine receptors are distributed in the cerebral

promazine. Peroutka et al17). reported on the anti-ƒ¿1 cortex and the limbic system. This type of receptor is receptor activity of drugs. Their data is similar to that reported to be associated with sleep-wake schedule, obtained in the present study. No reports prior to the suppression of convulsions, and regulation of appetite

present study have dealt with the affinity of properi- and body temperature5o. Histamine receptors can be ciazine, clotiapine, timiperone, or sultopride for ƒ¿1, divided into three types : H1, H2 and H3. Drowsiness receptors. is induced by blockade of H, receptors. α2 receptorsareautoreceptorsofnoradrenergic In the present study, mosapramine and per- neurons of the locus coeruleus.46) Stimulation of this phenazine showed high affinity for H1 receptors. This receptor is said to suppress the neuron activity. In the probably explains the high incidence of drowsiness present study, the Ki of most drugs for ƒ¿2, receptors was during mosapramine therapy. The affinity of pheno- between 10 nM and 100nM. Clocaparamine, carpi- thiazines for H1 receptors was higher than the affinity pramine, fluphenazine, and perphenazine had relative- of butyrophenones. This is not surprising in view of ly high affinity (Ki below 100nM). These drugs are the fact that phenothiazines were originally developed reported to improve negative symptoms, without reduc- as antihistaminics. ing the level of consciousness. They seem to exert this According to past reports on the incidence of activity by blocking the ƒ¿2, receptor. convulsions during antipsychotic drug therapy, treat- 97

The affinity of antipsychotic drugs for receptors

ment with chlorpromazine, levomepromazine, and II. Clinical applications zotepine is associated with high incidences. In the The same as behavioral-pharmacology experiments, present study, mospramine and perphenazine showed the performance of receptor binding experiments is a high affinity for H1 receptors, the same as chlorprom- routine procedure in the process of developing of azine. However, few cases of convulsions during treat- psychotropic agents. A great deal of data have been ment with mosapramine or perphenazine have been accumulated in receptor binding experiments. In reported. Thus, the results of the present study con- Japan, however, few reports of receptor binding experi- cerning H, receptor blockade are not consistent with ments carried out on currently used drugs under the the clinical incidence of convulsion. It therefore seems same experimental conditions have been published. In likely that the convulsions induced by antipsychotic other countries, a number of reports of such experi- agents involve some mechanism other than blockade of ments involving antipsychotic agents have been publi- H, receptors. shed, but many of these experiments have not involved Prior to the present study, Hill et al20). reported on any drugs used in Japan. With this in mind, we the anti-histamine action of various drugs. Their data performed receptor binding experiments on many are similar to those obtained in the present study. No drugs used in Japan under identical experimental reports prior to the present study have dealt with the conditions. Although the present study did not exam- affinity of clotiapine, zotepine, timiperone, carpi- ine all types of receptors identified, the data obtained pramine, or sultopride for H1 receptors. in this study will be clinically useful in assessments of F Sigma receptors the major efffects of antipsychotic agents. Clinical Sigma receptors are distributed in the cerebral application of the data obtained will be discussed in cortex and the hippocampus. This receptor as well as terms of the three aspects below.

μandχreceptors had been hypothesized to be A. Classification of antipsychotic agents receptors52), but at present, it is considered to be The classification shown in Table 3 overlaps the nonopioid receptor. Blockade of ƒÐ receptors has been classification based on chemical structures, except for considered to have an antipsychotic effect for the fol- fluphenazine. This classification will be useful in the lowing reasons : (1) antipsychotic agents have affinity following clinical settings. for ƒÐ receptors ; and (2) some opiates serve as 6 (1) When selecting drugs according to the stage and induce . A recent report, how- of the disease ever, states that mental symptoms induced by opiates 1) Acute stage are mediated by ƒÔ receptors53). Thus, the relationship Major symptoms seen in this stage are positive between o receptors and antipsychotic actions is un- symptoms such as hallucinations and delusions. Drugs clear. with high affinity for D2 receptors should be selected In the present study, haloperidol and fluphenazine to suppress these symptoms. Drugs belonging to the were found to have high affinity for ƒÐ receptors, three anti-DA receptor activity dominant groups consistent with previous reports. Despite a previous (Group A through Group C) are recommended. These report that atypical antipsychotic agents have high include haloparidol, bromperidol, fluphenazine, affinity for 6 receptors54), the affinity of SM-9018 for timiperone, and pimozide. this type of receptor was found to be low in the present 2) Chronic stage study. Major symptoms in this stage are negative symp- The data we obtained concerning anti-ƒÐ action toms such as avolition and affective flattening. Drugs were similar to those reported by Tam et al22), except with high affinity for 5HT2 receptors should be that the affinity of chlorpromazine and perphenazine selected to suppress these symptoms. Drugs belonging was lower than found by Tam et al. in guinea pig to Group D (one of anti-5HT receptor activity domi- brains, and that in the present study the affinity of nant groups) are recommended. These include carpi- chlorpromazine was higher than that of pimozide and pramine, chlorpromazine, levomepromazine, clotia- thioridazine. These two differences in results between pine, propericiazine, perphenazine and thioridazine. the present study and the study by Tam et al. are 3) Subacute to subchronic stage (mixed stage)

probably due to the species difference (rat and guinea Hallucinations and delusions have subsided, and

pig). No reports prior to the present study have dealt anxiety, hypochondriasis, and depressed mood are the with the affinity of clotiapine, zotepine, or oxypertine major symptoms in this stage. Drugs with high affinity for ƒÐ receptors. for D2 and 5HT2 receptors should be selected to sup- press these symptoms. Drugs belonging to Group E (one of anti-5HT receptor activity dominant groups) 98

Yonemura, Miyanaga, Machiyama

are recommended. These include mosapramine, cloca- ducing EPS. EPS is thought to involve not only the pramine, zotepine, and oxypertine. balance between anti-DA and anti-Ach actions, but (2) When selecting combined drug therapy anti-5HT actions. This view is based on the report It seems rational to select drugs from different that DA transmission in the nigrostriatal pathway is groups for combined therapy. Drugs belonging to the improved by blockade of 5HT2 receptors and stimu- same group have similar pharmacologic profiles, and lation of 5HT1A receptors. It has not yet been fully combined use of these drugs will have no effect other clarified how antipsychotic agents act on 5HT1A recep- than to increase the dose level of the drug initially tors, and thus this summary will include D2, Ach, and used. 5HT2 receptors, but exclude 5HT1, receptors. (3) When using a combination of drugs with the Fig.2 shows the total affinity for 5HT2 and Ach same affinity profile as unapproved drug. receptors of drugs that suppresses EPS (positive, i.e., The affinity profile of a given drug can be re- upward part) and the affinity for D2 receptors that produced by combining two or more other drugs induces EPS (negative or downward part) in graph having similar profiles. For example, the profile of an form. The downward part is marked for fluphenazine, unapproved drug can be reproduced by combining approved drugs with similar profiles. In fact, we have Table 4. pKi value ratios (5HT2/D2) succeeded in treating some cases by using a cocktail of drugs whose profile resembles that of olanzapine7). This method will become more widely applicable when data concerning etc5), as well as antipsychotic agents, are included. B. Drug therapy based on the concept of SDA for the treatment of chronic or intractable cases of schizophrenia in which negative symptoms pre- dominate Pharmacologic studies of (an atypical antipsychotic drug) have revealed a clinical phenome- non in which negative mental symptoms are reduced by strong blockade of 5HT2 receptors. This finding led to proposal of the concept of serotonin-dopamine antagonists (SDA)55). Matsubara et al.56) used the ratio of the affinity for 5HT2 to affinity for D2 re- ceptors (pKi) to distinguish agents from atypical antipsychotic agents (pKi > 1.2). If the data obtained in the present study are used, the 5HT2/D2 ratio is less than 1 for the butyrophenones (haloperidol, bromperidol, timiperone) and fluphen- azine, and greater than 1.2 for levomepromazine, thio- ridazine, propericiazine, and clotiapine (Table 4). Although the present study did not involve any atypical antipsychotic agents, the drugs mentioned above can be regarded as SDAs defined by Matsubara et al.56). The 5HT2/D2 ratio of antidepressants5) also ranged between 0.8 and 1.5, as we reported elsewhere. It can therefore be concluded that antidepressants as well as the drugs in Group D may be useful in treating cases with negative symptoms. C . Side effects of antipsychotic agents The type and dose level of drugs, the background variables of the patient (age, sex), and other factors are known to be associated with the onset of extrapy- Atypical antipsychotics have higher ratios than typical anti- ramidal symptoms (EPS). This paper will summarize psychotics ; i.e. the former have a stronger affinity for 5HT2 the potency of individual antipsychotic agents in in- receptors. 99

The affinity of antipsychotic drugs for receptors

Fig. 2 Profiles of affinity for receptors thought to be related to EPS

Total affinity for 5HT2 receptors and Ach receptors were considered to be the potency for the anti-extrapyramidal symptoms (EPS). Tendency to cause EPS were identified by comparing this potency with ant-D2 action. timiperone, haloperidol, bromperidol, and benz- promazine maleate, thioridazine HCl, propericiazine, amides. These drugs are likely to cause EPS and need perphenazine maleate, fluphenazine maleate, to be carefully used in clinical cases. Phenothiazines clotiapine, zotepine, haloperidol, timiperone, bromperi- usually show high affinity for 5HT2 and Ach receptors dol, pimozide, carpipramine HCl, clocarpremine HCl, and suppress EPS. However, only fluphenazine in this oxypertine, sulpiride, sultopride HCl, mosapramine, family seems likely to cause EPS, because its affinity nemonapride, and SM-9018. for 5HT2 is lower than for D2 receptors. This is On the basis of the results of the assays, the drugs corroborated by the clinical report of an EPS inci- were classified into three anti-DA receptor activity dence close to 50% among patients treated with flu- dominant groups and two anti-5HT receptor activity phenazine57). Fig.2 suggests that butyrophenones are dominant groups. This classification is expected to likely to induce EPS, but the incidence of EPS in provide a theoretical basis for selection of drugs in clinical cases was not high (between 10% and 50%). clinical cases. Extrapyramidal symptoms, which are This discrepancy is probably attributable to some often observed as adverse reactions to antipsychotic other factors such as dose level. drugs, have been discussed in relation to the affinity for EPS are the most important adverse reaction that relevant receptors. needs so be borne in mind when using antipsychotic agents. To avoid this adverse reactions, it is recom- Acknowledgments : The author is indebted to the mended that Fig.2 be consulted when selecting antipsy- pharmaceutical companies for supplying the test drugs. chotic agents. The author's thanks are also extended to the Institute for Drug Discovery Research of Yamanouchi Pharma- CONCLUSION ceutical Co.,Ltd. for their supply of human D3 rece- Radioreceptor assays were performed on antipsy- ptor expressing CHO cells. This study was funded by chotic agents that are frequently used in Japan. The a part of grant from the Pharmacopsychiatry Research affinity of these drugs for 12 receptors was examined to Foundation. provide pharmacologic spectra. The receptors REFERENCES examined were D1, D2, D3, D4, 5HT2, 5HT3, 5HT1A

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