Pharmacological Reports Copyright © 2006 2006, 58, 626–635 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences

Effect of BD 1047, a sigma1 receptor antagonist, in the animal models predictive of antipsychotic activity

Gra¿yna Skuza, Zofia Rogó¿

Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland

Correspondence: Gra¿yna Skuza, e-mail: [email protected]

Abstract: The sigma receptors were first classified as a subtype of opioid receptors but later they were found to be a distinct pharmacological entity. Many preclinical and clinical data have indicated that sigma receptor ligands have to be involved in neuropsychiatric disorders, including schizophrenia. Numerous data have suggested that potential antipsychotic activity of sigma ligands results from their „antagonistic” activity. However, the subcellular mechanisms by which sigma ligands exert their effects have not been elucidated in detail, therefore, the terms “agonist” or “antagonist” and their functional implications are not entirely unequivocal. The aim of the present study was to find out if BD 1047, described recently as a selective functional antagonist of sigma receptors, shows antipsychotic activity in animal models predictive of efficacy in schizophrenia. In contrast to rimcazole and panamesine, two selective sigma ligands whose antipsychotic activity was confirmed clinically, BD 1047 did not decrease amphetamine-induced hyperactivity in mice in a statistically significant manner. Likewise, it did not modify the hyperactivity induced by NMDA receptor antagonists, phencyclidine, memantine or dizocilpine. On the other hand, BD 1047 attenuated apomorphine-induced climbing in mice and phencyclidine-induced head twitches in rats, like rimcazole and panamesine did. Summing up, BD 1047 shows a moderate activity in models used in this study suggesting that its usefulness as an antipsychtic drug is doubtful. However, more detailed studies are required for definitive confirmation of this conclusion.

Key words: BD 1047, sigma receptor antagonist, antipsychotic activity

Introduction suggested soon after their discovery. Benzomorphan derivatives with high affinity for s receptors are known to produce hallucinations, dysphoria and de- The sigma (s) receptors were first proposed by Mar- personalization. On the other hand, many neuroleptics tin et al. [18] as a subclass of opioid receptors, later exhibit high affinity for s sites. For several years ha- confounded with the high affinity phencyclidine loperidol had remained the ligand with the highest af- (PCP) binding sites. Now, it is well established that s finity for s receptors and had been thus used in most receptors are unique binding sites, distinct from opi- of the radioligand binding studies. Furthermore, the ate and PCP receptors, which are implicated in higher selective loss of cerebral cortical s binding sites in brain functions [5, 10, 29, 34]. A potential involve- schizophrenic patients was reported [35]. Finally, the s s ment of receptors in psychotic disorders was first recent demonstration of an association between the 1

626 Pharmacological Reports, 2006, 58, 626–635 Potential antipsychotic activity of BD1047 Gra¿yna Skuza et al.

receptor gene polymorphism and schizophrenia sup- for s sites, was applied to study the possibility of po- ports the idea that these receptors may play a role in tentiation of BD 1047 effect in a representative test pathogenesis of this disease [14]. (apomorphine-induced climbing in mice) [6, 11–13, 17]. s s The receptors are classified into two subtypes, 1 s and 2 receptors, of which the first was cloned from rodent and human tissues [25, 26] while the second s has not yet been fully characterized. The 1 sites are particularly abundant in the hippocampal formation Materials and Methods and other limbic areas (involved in cognition and s emotion) while the highest densities of 2 receptors were revealed mostly in regions related to motor func- The experiments were carried out on male Albino tions (cerebellum, red nucleus, superior colliculus, Swiss mice (ca. 50 days old, weighing 25–28 g) and various cranial nerve nuclei and in substantia nigra Wistar rats (ca. 80 days old, weighing 250–300 g) and striatum). Although the precise mechanism of the housed in groups (20 or 6 per cage, 35 × 55 × 20 cm, functional response of these receptors is still uncer- respectively) under a controlled environment at a tem- tain, it is accepted that s receptors can modulate perature of 22 ± 2°C on a 12-h light/dark cycle (the a number of central neurotransmitter systems, includ- light on at 7 a.m.). The animals had free access to ing glutamatergic and dopaminergic ones [5, 8, 10, 20]. food and water. The studies were conducted between In the last 15 years, a number of compounds with 8 a.m. and 3 p.m. Experimental protocols were ap- a high affinity and selectivity for s binding sites have proved by the Local Bioethics Commission and com- been discovered and investigated for their antipsy- plied with the guidelines of the agency in charge at chotic potential. Some of these compounds (but not the Institute of Pharmacology, Polish Academy of all) are defined as s receptor antagonists (e.g. rimca- Sciences. zole, BMY 14802, NE-100) and are effective in ani- mal models predictive of antipsychotic activity [5, 29]. The therapeutic value of s ligands in schizophre- Substances nia has not been clearly established but preclinical s and clinical data have suggested that 1 receptor D-amphetamine sulfate (AMP, Sigma, USA); apo- ligands alleviated negative symptoms in schizo- morphine hydrochloride hemihydrate (APO, Sigma- phrenic patients [12]. Panamesine is one of a few Aldrich Chemie GmbH, Germany); BD 1047 compounds currently under clinical trials [13]. (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethyl- Recently, two selective s ligands, BD 1047 and BD amino)ethylamine, Tocris, UK); clozapine (Pharma- s s o 1063, which bind preferentially to 1, but also to 2 ceutical Institute, Poland); 1,3-di- -tolylguanidine receptors, were described [19, 32]. They antagonized (DTG, Research Biochemicals Int., USA); dizocilpine the effects induced by microinjections of s „ago- (/+/MK-801, hydrogen maleate, Research Biochemi- nists”, DTG and haloperidol, into the red nucleus (tor- cals Int., USA); memantine hydrochloride (Sigma- ticollis) and into the facial or spinal trigeminal nu- Aldrich Chemie GmbH, Germany); panamesine cleus (vacuous chewing and facial tremors) in rats. (EMD 57445, Merck KGaA, Germany); phencyclidine The aim of this study was: firstly, to find out if a se- (PCP, Research Biochemicals Int., USA); rimcazole di- lective functional antagonist of the s receptor, BD hydrochloride (Research Biochemicals Int., USA). 1047, shows antipsychotic activity in commonly used All the compounds were dissolved in distilled wa- animal models predictive of efficacy against the ter (except for DTG, which was suspended in 1% symptoms of schizophrenia; secondly, to confirm (or Tween 80) and administered perorally (po, not) the idea that potential antipsychotic effects of s panamesine), subcutaneously (sc, AMP, APO) or ligands are a common feature of antagonists of these intraperitoneally (ip) in a volume of 10 ml/kg to mice sites. Rimcazole (one of the first s ligands tested clini- and 2 ml/kg to rats. cally as antipsychotic compound) and panamesine The doses and way of administration of BD 1047, (a potent s receptor ligand with functional antidopa- rimcazole and panamesine were chosen on the basis minergic profile) were used as reference compounds, of the literature data and our earlier studies [ 17, 27, clozapine, an atypical antipsychotic devoid of affinity 28, 33].

Pharmacological Reports, 2006, 58, 626–635 627 * p<0.05vs . vehicle The locomotor hyperactivity induced by A.1 1600 * D-amphetamine (AMP), phencyclidine (PCP), 1400 dizocilpine and memantine in mice 1200 * The locomotor activity was measured in photoresistor 1000 actometers (two light beams; 10 cm high, 30 cm in di- 800 ameter) in which mice were placed individually. Ani- 600 mals were pretreated with BD 1047, rimcazole, or 400 panamesine 30 min before AMP (2.5 mg/kg), PCP 200 (3 mg/kg), dizocilpine (0.2 mg/kg) or memantine 0

Activity counts (mean ± SEM) (10 mg/kg). After successive 30 min, mice were D-AMP – 2.5 2.5 2.5 2.5– 2.5 2.5 – – –– placed in actometer cages. The measurement of loco- BD1047 0.5 1 3 10 motor activity lasted for 1 h. Each group consisted of A.2 120 6–8 mice. AMP (2.5 mg/kg) 100

Apomorphine (APO)-induced climbing behavior 80 in mice 60

For observation, mice were placed in separate cylin- 40 drical cages (12 cm in diameter, 14 cm high) with

(% of inhibition) 20 walls made of metal bars (2 mm in diameter, 1 cm 0 apart). APO, 3 mg/kg sc, was injected 60 min after the Amphetamine hyperactivity BD 1047 0.5 1310[mg/kg] drugs. Twenty minutes after injection of APO, time of climbing was determined for 2 min. Climbing time was B 700 * * p < 0.001vs . vehicle defined as the period during which the animal held the 2, # p < 0.001vs . AMP 600 3 or 4 paws on the wall. Groups consisted of 8 mice each. 500 # # Phencyclidine (PCP)-induced head twitches in rats 400

300 Rats were placed individually in wire cages (22 × 22 × 24 cm) for observation. Drugs were given ip, 1 h before 200 PCP (5 mg/kg ip). From 10 min after administration 100 of PCP, head twitches was counted for 2 min at inter- Activity counts (mean ± SEM) 0 vals of 10 min for a total of 60 min. Groups consisted D-AMP – 2.5 2.5 2.5 RIM ––10 20 of 6 rats each. C 700 * * p < 0.001vs . vehicle # p< 0.001vs . AMP Data analysis 600 500

The data were evaluated by ANOVA, followed, when 400 # appropriate, by individual comparisons with the con- # 300 trol using Dunnett’s test. 200

100

0 Activity counts (mean ± SEM) D-AMP – 2.5 2.5 2.5 Results PAN ––0.5 1

Fig. 1. The effect of BD1047 (A), rimcazole, RIM (B) and panamesine, AMP-induced locomotor hyperactivity in mice PAN (C) on the D-amphetamine (AMP)-induced locomotor hyperactiv- ity in mice. BD1047, RIM (both ip) and PAN (po) were given 60 min, and AMP 30 min before the test. The locomotor activity was counted AMP (2.5 mg/kg, sc) increased the locomotor activity for 1 h. Results are expressed as the means ± SEM (activity counts – in mice up to ca. 240% (vs. vehicle group). BD 1047 A.1, B and C or percent of amphetamine group – A.2) (n = 8–10)

628 Pharmacological Reports, 2006, 58, 626–635 Potential antipsychotic activity of BD1047 Gra¿yna Skuza et al.

A 120 * p < 0.001vs . APO APO-induced climbing behavior in mice 100 * APO (3 mg/kg) evokes climbing behavior of ca. 100 s 80 duration. BD 1047 at the dose of 10 mg/kg decreased the APO-induced climbing. The lower doses of BD 60 1047 (1 and 3 mg/kg) did not change the time of Time (s) 40 climbing induced by APO (Fig. 2A). Rimcazole at the dose of 20 mg/kg attenuated the 20 apomorphine-induced climbing behavior in mice, 0 whereas its lower doses (5 and 10 mg/kg) were inef- APO 3 33 3 fective (Fig. 2B). BD 1047 – 1310[mg/kg] Panamesine, 0.5 and 1 mg/kg, decreased the climb- ing behavior in mice in statistically significant man- B 140 ner by ca. 40–60% (Fig. 2C). * p < 0.05vs . APO 120 100 * vs 80 A 120 * p < 0.05 . APO 60 100

Time (s) 40 * 80 20

0 60 APO 3333 – [mg/kg] Time (s) RIM 5 10 20 40

C 120 20 * p < 0.001vs . APO 100 0 80 * APO 333 CLOZ – 10 20 [mg/kg] 60 * B 120 40

Time (s) 100 20 80 0 APO 3 3 3 60 PAN – 0.5 1 [mg/kg]

Time (s) 40 Fig. 2. The effect of BD1047 (A), rimcazole, RIM (B) and panamesine, PAN (C) on the apomorphine (APO)-induced climbing in mice. 20 BD1047 and RIM (ip), as well as PAN (po) were given 1 h before APO (sc). Twenty minutes after APO injection, time of climbing was deter- mined for 2 min. Results are expressed as the means ± SEM 0 (n = 8–10) APO 3333 BD 1047–– 3 3 CLOZ – – 10 10 [mg/kg] (1, 3 or 10 mg/kg, ip) did not modify the effect of

AMP (Fig. 1A). Rimcazole (10 and 20 mg/kg) and Fig. 3. The effect of co-administration of BD 1047 and clozapine panamesine (0.5 and 1 mg/kg) antagonized AMP- (CLOZ) on the apomorphine (APO)-induced climbing in mice. CLOZ was given (ip) separately (A) or jointly with BD1047 (ip)(B) 1 h before induced locomotor hyperactivity (Fig. 1B and 1C, re- APO (sc). Twenty minutes after APO injection, time of climbing was deter- spectively). mined for 2 min. Results are expressed as the means ± SEM (n = 8–10)

Pharmacological Reports, 2006, 58, 626–635 629 * p<0.001 vs. vehicle 1000 A In a separate experiment, the interaction of BD * 1047 and clozapine was studied. Firstly, the inactive dose of clozapine (10 mg/kg) was chosen for the next 800 experiment (Fig. 3A). 600 Co-administration of inactive doses of BD 1047 (3 mg/kg) and clozapine (10 mg/kg) did not modify 400 the climbing behavior in comparison with the effect of both compounds given alone or with the control 200 (APO) group (Fig. 3B). Activity counts (mean ± SEM) 0 MK-801 – 0.2 0.20.2 0.2 BD 1047 – – 1 3 10 * p<0.001 vs vehicle 1400 A 1200 B * p < 0.001vs . vehicle 1200 * * 1000 1000 800 800

600 600 400 400 200 200 0 PCP – 3 3 3

Activity counts (mean ± SEM) BD1047 – – 3 10 [mg/kg] Activity counts (mean ± SEM) 0 MK-801 – 0.2 0.20.2 0.2 RIM – – 5 10 20 [mg/kg] ** vs 1400 * vs 1000 p < 0.001 . vehicle B p < 0.001 . vehicle C ** # vs * p < 0.001 . MK-801 1200 800 1000 600 800 # 600 400

400 200

200 0

Activity counts (mean ± SEM) – Activity counts (mean ± SEM) 0 MK-801 0.2 0.2 0.2 PCP – 3 3 3 3 PAN – – 0.5 1 RIM – – 5 10 20 [mg/kg]

Fig. 5. The effect of BD1047 (A), rimcazole, RIM (B) and 1400 C * vs panamesine, PAN (C) on the MK-801 (dizocilpine)-induced locomo- * p < 0.001 . vehicle tor hyperactivity in mice. BD1047, RIM (both ip) and PAN (po) were 1200 given 60 min, and MK-801 30 min before the test. The locomotor ac- 1000 tivity was counted for 1 h. Results are expressed as the means ± SEM (n = 8) 800 600 400 PCP-induced locomotor hyperactivity in mice 200 0 PCP at the dose of 3 mg/kg induced the locomotor hy-

Activity counts (mean ± SEM) PCP – 33 3 PAN ––0.5 1 peractivity in mice. BD 1047 at doses of 3 and 10 mg/kg did not modify this effect of PCP (Fig. 4A). Similar lack of the activity was observed after rimcazole Fig. 4. The effect of BD1047 (A), rimcazole, RIM (B) and panamesine, PAN (C) on the phencyclidine (PCP)-induced locomo- at 5, 10 or 20 mg/kg (Fig. 4B). Panamesine at low doses tor hyperactivity in mice. BD1047, RIM (both ip) and PAN (po) were given 60 min, and PCP 30 min before the test. The locomotor activity (0.5 and 1 mg/kg) only slightly and not significantly at- was counted for 1 h. Results are expressed as the means ± SEM (n = 8) tenuated the PCP-induced hyperactivity (Fig. 4C).

630 Pharmacological Reports, 2006, 58, 626–635 Potential antipsychotic activity of BD1047 Gra¿yna Skuza et al.

* p<0.001vs .PCP Dizocilpine-induced locomotor hyperactivity in 140 A mice 120 PCP Dizocilpine (MK-801) at the dose of 0.2 mg/kg in- 100 ------duced the locomotor hyperactivity in mice (by ca. 80 200% vs. vehicle group). Neither BD 1047 (1, 3 and 60 * 10 mg/kg) (Fig. 5A) nor rimcazole (Fig. 5B) modify

(% of control) this effect of MK-801, while panamesine (0.5 and 40

Number of episodes 1 mg/kg) decreased it (Fig. 5C). 20

0 PCP 5 5 5 * p<0.001 vs. vehicle BD 1047 0.5 1 3 [mg/kg] 1000 A vs * *p<0.05 **p<0.001 .PCP 800 120 B PCP 100 ------600 80 400 * 60

200 40 **

(% of control) 0 20 MEM – 10 10 10 10 Number of episodes Activity counts (mean ±BD SEM) 1047 – – 1310 0 PCP 5 5 B * p < 0.001vs . vehicle RIM 10 – [mg/kg] vs PAN – 5 800 * # p < 0.001 . MEM

# Fig. 7. The effect of BD1047 (A) or rimcazole, RIM and panamesine, # 600 PAN (B) on the phencyclidine (PCP)-induced head twitches in rats. BD1047 and RIM (ip), as well as PAN (po) were given 1 h before PCP (ip). Beginning at 10 min after PCP administration, the number of 400 head twitches was counted for 2 min at 10-min intervals for a total of 60 min. Results are expressed as the means ± SEM (percent of PCP group) (n = 6) 200

0 – Activity counts (mean ± SEM) MEM 10 10 10 RIM ––10 10 Memantine-induced locomotor hyperactivity in mice * p < 0.001vs . vehicle 800 C * # p< 0.001vs . MEM Memantine (10 mg/kg) increased the locomotor activity of mice up to ca. 280% of control. BD 1047 at doses of 600 1, 3 and 10 mg/kg, did not modify this effect of meman- tine (Fig. 6A). Rimcazole (10 and 20 mg/kg) and, to 400 a greater extent, panamesine decreased the locomotor # hyperactivity induced by memantine (Fig. 6B and 6C, 200 # respectively).

0 MEM – 10 10 10

Activity counts (mean ± SEM) PCP-induced head twitches in rats PAN – – 0.5 1 PCP (5 mg/kg) induced episodes of head twitches in Fig. 6. The effect of BD1047 (A), rimcazole, RIM (B) and rats. Only one dose of BD 1047, 1 mg/kg, decreased panamesine, PAN (C) on the memantine (MEM)-induced locomotor hyperactivity in mice. BD1047, RIM (both ip) and PAN (po) were the number of head twitches in statistically significant given 60 min, and MEM 30 min before the test. The locomotor activity was measured for 1 h. Results are expressed as the means ± SEM manner (Fig. 7A). Lower (0.5 mg/kg) and higher (n = 8) (3 mg/kg) doses of BD 1047 were ineffective.

Pharmacological Reports, 2006, 58, 626–635 631 Rimcazole and panamesine decreased the number that BD 1047 did not modify AMP-induced hyperac- of PCP-induced head twitches in rats – the lowest tivity in mice but it counteracted APO-induced climb- doses showing statistically significant effect were 10 ing. It is widely accepted that s receptor ligands are and 5 mg/kg, respectively (Fig. 7B). able to modulate dopamine neurotransmission by in- fluencing dopamine outflow [2, 8, 9, 21, 22]. Moreo- ver, some s ligands modulate the activity of dopamin- ergic neurons [e.g. 23, 24]. As has been found earlier [3], a good correlation between blockade of dopamine Discussion receptors in the hippocampus and antagonism of APO-induced climbing in mice is a common feature The most of s receptor ligands tested as potential an- of both classical and atypical neuroleptics while no tipsychotic drugs were classified as s “antagonists”, correlation was observed between blockade of dopa- since some of them attenuated the dystonia (torticol- mine receptors in the striatum and climbing when lis) induced by s „agonists” (e.g. DTG, (+)pentazo- atypical antipsychotics were used. It is suggested that cine) after their injection into the red nucleus of rats. neuroleptics preferentially blocking hippocampal dopa- The red nucleus has proven to be a useful site for in- mine receptors may allow for a better dissociation between vestigating the potential role of s receptors, since it antipsychotic efficacy and induction of extrapyramidal side contains high concentrations of these receptors. The effects in the clinical practice. Thus, the inhibitory effect of potency of s ligands to produce dystonia in rats is BD 1047 on the apomorphine-induced climbing behavior closely correlated with their ability to displace in mice may be due to its indirect influence on the dopa- [3H]DTG from rat brain membranes [10, 29, 34]. minergic transmission in the hippocampus, indicating that s Moreover, several 1 ligands potentiated the neuronal the compound possesses atypical profile. response to N-methyl-D-aspartate (NMDA) in the As was mentioned in the Introduction, rimcazole s CA3 region of the rat dorsal hippocampus while other was the first selective ligand which has been sub- s ligands suppressed the potentiation of NMDA re- jected to clinical trial as a potential antipsychotic drug sponse induced by s agonists [4, 20]. However, the [11]. It was found to cause improvement of negative subcellular mechanisms by which s ligands induced symptoms but worsening of acute positive symptoms their effects have not been elucidated in detail, hence, [11, 12]. In the present study, rimcazole and – in the more the terms “agonist” or “antagonist” and their func- extent – panamesine, decreased both AMP-induced hy- tional implications are not entirely unequivocal. peractivity and climbing behavior induced by APO. Two selective s ligands, BD 1047 and BD 1063, PCP evokes schizophrenia-like symptoms in nor- were described previously as compounds, which bind mal humans. It has been accepted that it exerts the ef- s s preferentially to 1 (but also to 2) receptors. They at- fect on the mesolimbic dopamine system and modu- tenuated the dystonic postures following intrarubral lates dopamine function in the brain, the abnormality microinjections of DTG or haloperidol, as well as of which has been proposed to be one of the main pa- vacuous chewing and facial tremors observed after thology in schizophrenia. Moreover, the dysfunction microinjections of s agonists into the facial or spinal of glutamatergic neurotransmission may play an im- trigeminal nucleus in rats [19, 32]. These findings portant role in this disease. Therefore, various abnor- suggested that BD 1047 and BD 1063 acted as an- mal behaviors in animals produced by PCP (rearing, tagonists at s sites, thus it seems that they should pos- head weaving, hyperlocomotion, diving, disruption of sess the antipsychotic activity. pre-pulse inhibition) have been considered to be Commonly used experimental models predictive of a model for screening of antipsychotic activity [29]. antipsychotic drug action are based on testing their Most of the newly synthesized potential antipsy- ability to antagonize various effects of dopamine ago- chotics with affinity for s sites antagonized the effects nists and PCP. Such an effect was found for a number of PCP. It is worth adding that these compounds did of s ligands studied previously. They were revealed to not induce catalepsy [29]. It is believed that PCP- inhibit the effects of dopamine agonists (AMP, APO) induced head weaving is related to an activation of as well as PCP, despite lack of their direct interaction 5-HT1 (5-HT1A) receptors while head twitches are with dopamine or PCP receptors (e.g. rimcazole, NE- elicited by PCP interaction (direct or indirect) with 100, MS-377) [29]. The obtained results indicated 5-HT2 (5-HT2A) receptors [37]. It was shown that

632 Pharmacological Reports, 2006, 58, 626–635 Potential antipsychotic activity of BD1047 Gra¿yna Skuza et al.

s PCP markedly increased dopamine and serotonin re- 1 receptor binding, given subchronically [38]. On lease in the medial prefrontal cortex (microdialysis the other hand, panamesine, which exerted the most study) [30]. In the present study, BD1047, like rimca- potent effects in our studies, exhibited functional anti- zole and panamesine, attenuated the head twitches in- dopaminergic activity, as it was shown previously [17]. duced by PCP in rats. These activity seems to be indi- Even if the importance of BD 1047 as a potential rect, since none of the studied compounds show affin- antipsychotic agent is doubtful, this compound is able ity for 5-HT or PCP receptors in vitro [1, 6, 19]. to counteract some effects of cocaine (including hy- On the other hand, neither BD 1047 nor rimcazole peractivity, conditioned place preference and toxicity) or panamesine modified PCP-induced hyperactivity and it is promising (like some s antagonists) as medi- in mice. The capacity to increase motor activity is the cation in cocaine abuse [29]. s characteristic feature of NMDA receptor antagonists The effectiveness of ligands in schizophrenia has (especially uncompetitive, e.g. dizocilpine, meman- not been clearly established but available data (either s tine, PCP) which is thought, at least in part, to be the preclinical or clinical) have suggested that 1 receptor result of an activation of dopamine neurotransmission ligands are capable of abating negative symptoms in s in the corticolimbic structure [7, 16, 36], though re- schizophrenic patients [12]. The role of receptors in cent findings indicated that glutamate is also required schizophrenia requires further studies but it seems un- s for the locomotor effect of NMDA receptor antago- certain that potential antipsychotic activity of some ligands is correlated with their antagonistic activity at nists [31]. The lack of the influence on the locomotor s receptors. Nevertheless, s receptor ligands repre- hyperactivity induced by both amphetamine and sent a new class of therapeutic agents for psychiatric NMDA receptor antagonists (dizocilpine, memantine, disorders, worth further investigations. PCP) may suggest that BD1047 is devoided of influence on the corticolimbic dopamine transmission. On the con- trary, rimcazole and panamesine attenuated the hyperac- Acknowledgments: tivity induced by dizocilpine (MK-801) and memantine. The authors wish to express their thanks to Dr. Bartoszyk (Merck In view of rather weak effects of BD 1047 in mod- KGaA, Germany) for EMD 57445 and to Pharmaceutical Institute (Poland) for clozapine. els used in these paper, the possibility to increase its effect by clinically used neuroleptic clozapine was analyzed in apomorphine-induced climbing model. In contrast to the observation of Karasawa et al. 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receptors in reserpinized rats. Neuropharmacology, 1987, amino) ethylamine (BD 1047) alters sigma receptor 26, 1489–1497. binding. Eur J Pharmacol, 1997, 324, 39–47. 38. Zambon AC, De Costa BR, Kanthasamy AG, Nguyen BQ, Matsumoto RR: Subchronic administration of Received: N-[2-(3,4-dichlorophenyl)ethyl]- N-methyl-2-(dimethyl- February 22, 2006; in revised form: June 27, 2006.

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