P-4-15 Zotepine: Preclinical tests predict antipsychotic efficacy and an atypical profile

331

P-4 Antipsychotics." basic and clinical studies Drug affinities (Kis m nM) and ratios Antipsychotic

hD2

hD~

hD4

D2/D~

D2/D4

D$/D4

Haloperidol Raclopride Clozapine Risperidone Qlanzapine Sertindole Ocaperidone Ziprasidone Seroquel S 17828 S 16924

04 13 76 33 60 23 07 47 186 32 28 8

29 14 257 107 32 83 25 11 7 426 16 49

19 4365 35 62 26 18 3] 123 2344 20 62

01 09 03 03 02 03 03 04 04 20 06

02 <001 22 05 02 01 02 04 01 16 46

15 <0 01 73 17 12 05 08 10 02 08 79

Haloperidol exhibited higher affinity at hD 2 than hD 3 and hD 4 receptors and risperidone, olanzapine, sertindole, ocaperidone and zlprasidone all showed a similar binding profile. Raclopride, in contrast, did not distinguish hD 2 and hD 3 sites and, like seroquel, had low affinity at hD 4 sites. S 17828 was the only compound to exhibit higher affinity at both hD 3 and hD 4 versus hD 2 sites. Although clozapine showed a preference for hD4 receptors, the novel antipsychotic, S 16924, was 6-fold more potent than clozapine at hD4 sites and was 5-fold more potent at hD 4 than hD 2 receptors. In conclusion. the majority of antipsychotics display a preference for hD 2 vs hD3/hD 4 receptors. Nevertheless, S 17828 shows higher affinity at hD 3 and hD4 than hD 2 sites. Further, S 16924 exhibits, like clozapme, a preference for hD4 receptors and, in this respect, its hD 4 activity is reinforced relatively to that of clozapine. These properties may be of importance in view of the proposed implication of hD 4 and hD 3 receptors in schizophrenia.

Pharmacology of the potential antipsychotic EMD 57445 in animals and humans G.D. Bartoszyk 1 H,M. Bender 2, A Heusener 3, C. Schnorr 4 1E. Merck Pharmaceutical Research. Department of CNS-Research. 64271 Darmstadt, Germany. 2 institute for Pharmaeokmet~cs and Metabolism, 85567 Grating, Germany. 3 E. Merck Pharmaceutical Research, Department of Toxicology, 64271 Darmstadt. Germany," 4 E. Merck Pharmaceutical Research. Department of Clinical Pharmacology, 64271 Darmstadt, Germany The selective sigma-ligand EMD 57445 ({5S)-(-)-5-[4-hydroxy-4-(1,3-benzod~oxol-5-yl)+piperidin 1-yl methyl]-3~4-methoxyphenyl)-oxazGidin-2-one, HCI) is a drug with pronounced functional antidopaminerglc actiwty and eft1 cacy in animal models (Bartoszyk et al, 1992). In the dose range indicative for antipsychotic actwity (1-5 mg/kg po} EMD 57445 had no effects on general behavior in mice and rats, At higher doses (30-100 mg/kg po) EMD 57445 showed some sedation, hypnotic effects, and weak antichohnerp~c effects; EMD 57445 had no effects on the cardiovascular system EMD 57445 showed low acute toxicity (LD50walues in m g / k g 1 1 6 7 p o u n d 1054 ip in rats, and 566 po and 600 ip m m~ce) Side effects in man (39 male volunteers, double-blind, placebo-controlled, randomized trial) were classified using the WHO Adverse Reaction Dictionary, Ciba-Geigy Version. Compared to placebo, no dose-dependency of the adverse events was observed for EMD 57445 after single oral administration (1-30 rag). EMD 67445 was well tolerated up to the highest apse of 30 mg. Drug-related events were mostly mild and consisted of headache (2 subjects of 6 at 3 rag). tiredness (2/6 at 15 mg and 1/6 at 30 mg). thirst and flatulence (1/6 at 1 rag), diarrhoea (2/6 at 1 mg and 3 mg), and nausea (2/6 a t 3 m g ) Pharmacokinetics are summarized in the table Safety and tolerability of a dose of 10 mg of EMD 57445 administered once daily f o r 7 consecutive days was studied in 12 male volunteers Maximal plasma concentration were found after 1-2 h; steady state was reached after the third administration Compared to the first day, on d a y 7 a s l i g h t i n crease in AUC and terminal half-life was determined Adverse events (10/12 subjects) were the same as reported m the single administration study. In both phase 1 clinical studies, the overall assessment by the investigators and the subjects was generally good or very good The physical examinations, cardiovascular parameters, sp~rometry, and laboratory tests did not result in any clinically relevant changes. Pharmacokinetics of EMD 57445 were studied in vanous species including man after single oral administration The pharmacokinet~c parameters are summarized in the table

Species

Dose

Cmax [ng/ml]

tmax [hi

tl ,,2 [hi

AUC0~ [hxng/ml]

Bioavailability

Mouse Rat Dog Monkm/ Man Man Man Man Man

3 mg/kg 3 mg/kg 5 mg/kg 5 mg/kg 1 mg 3 7 mg 15 mg 30 mg

266 160 450 398 09 50 157 37.7 84.5

025 05 2 05-2 1.2 2.5 15 1.4 15 13

03 08 14 08 83 32 54 38 64

2360 676 1710 2220 105 21 5 67 7 1937 440

41% 33% 65% 54%

EMD 57445 is a potential antipsychotic drug which is well tolerated in animals and man. EMD 57445 is currently evaluated in first phase II clinical studies.

References Bartoszyk, G Dr Greiner, HE.. Hatting, J., Stohrer, M , Seyfried, C A (1992) Pharmacological profile of the atypical neuroleptic drug EMD 57445 Soc Neurosci. Abstr 18, 548

Zotepine: preclinical tests predict antipsychotic efficacy and an atypical profile P L Needham, M.J. Skill, D.J. Heal. Boots Pharmaceuticals Research Department, Nottingham NG2 34.4 UK Zotepine (ZOT) ~s an atypical antipsychotic drug which is in clinical trial in both the USA and Europe. ZOT has been shown to be effective in the treatment of the positive and negative symptoms of schizophrenia and to have a low propensity to produce extrapyramidal side-effects (M011er. H.J. and Moiler, W.E, 1994; Petit, M et al, this meeting). In this study, w e have defined the pharmacological profile of ZOT in a range of well established preclinical tests which are predictive of antipsychotic efficacy and side-effect potential, and compared with it those of the atypical antipsychotic, clozapine {CLOZI, and two typical drugs, chlorpromazine (CPZ) and hatoperidol (HAL). Apomorphme (1 mg/kg sc) climbing (AC) was measured in CD1 mice. Locomotor responses to amphetamine (2.5 mg/kg sc; LOCO) were measured in CD rats. Catalepsy (CAT) to ZOT, CLOZ, CPZ and HAL was also measured in CD rats. ZOT potently inhibited apomorphine-induced climbing in mice. It had a very ,ong duration of action (>>6 h) when given orally and increased in potency four-fold, between 0.5 and 4 hours after administration. HAL maintained its activity during this time, but those of CLOZ and CPZ were reduced at 4 hours. In rats, ZOT showed potent, long-lasting inhibition of amphetamine hyperactivity, but its liability to induce catalepsy rapidly declined, providing a wide 'therapeutic w i n d o w ' between 'antipsychotic" and 'side-effect' activity. Catalepsy is an excellent model of idiopathic parkinsonism and, thus, predicts a low incidence extrapyramidai side-effects with ZOL As expected, the anti-amphetamine activity of CLOZ was also well separated from its cataleptic liability, whereas the two typical drugs, CPZ and HAL. show little separation of these activities. Pharmacological profile of zotepine and comparator drugs ZOT

CLOZ

CPZ

HAL

AC (Do)

T,me 05 4

98 20

95 38

5.1 77

0.3 0.3

LOCQ 'dP)

1 4

07 05

43

17

CAT (p)

1 4

33 12 5

Rat,o CAT/LOCO

0.1 38 -

1 45 88 4 245 Data are ED50's (mp/kgl: Time - time post-dose (hours)

44 0.4 26 4

These results argue that ZOT will be a potent antLpsychotic when given e~ther orally or parenterally and provide the first pre-clinical evidence to support the reported atypical profile of ZOT in the clinic (MQIler. H,J. and Moiler. W.E, 1994; Petit, M et al., 1995). The receptors which may contribute to this atypical activity have been investigated by profiling zotepine's affinities for the human dopamine receptor subtypes (Needham et al, this meeting).

References Muller, H-J and Moiler, WE {1994) Zotepine - - evaluation and possibilities for development Nervenarzt, 65 {Suppl). 2~}

332

P-4 Antipsychotics: basic and clinical studies

Needham PL.. Atkinsorl, J and Heal, DJ {1995} Binding of zoteplne and other antlpsy chotics to cloned human dopamine receptors (this meeting) Petit, M , Raniwalla, J. Leutenegger, E , Tweed, J A and Kelly, F (1995) A double-bhnd study of zotepine vs haloperidol in schizophrenia (this meeting)

~ - ~

Binding of zotepine and other antipsychotics to cloned human dopamine receptors

PL Needham, J Atkinson, D J Heal Boots Pharmaceuticals Research Department, Nottingham NG2 3,4,4 UK There is now clear evidence to show that dopamine transmits its second messenger effects via a family of receptor subtypes. Recently, molecuiar cloning and sequence homology studies have revealed the existence of at least five distinct dopamine receptor subtypes, viz D 1 to D5 m two receptor subfami/ies, ie D 14ike and D2-1ike Zotepine ~san atypicalantipsychot~c drug (Muller, H J , and Mdller, W.E. 1994; Petit. M. et al., 1995) which is in chnical trial in both the USA and Europe. To provide a greater insight into zotepme's atypical antipsychotic action, we have now defined its binding profile to cloned human D 1, D 2, D 3, D42 and D 5 receptors and have compared tt with those of the following ant~psychofics: atypical, clozapine, typical, haloperidol and the newly introduced D2/5*HT 2 antagonist, nspendone. Binding experiments were conducted using commercial}y availab}e cloned human receptors (RBI, Natick, MA): D 1 (SF-9 cells) labelled with 1 nM [3H]SCH 23390 defined by 100 /~M chlorpromazine; D 2 {SF-9 cells) 1 nM [3H]sulpiride defined by 10 nM spiperone: D3 (CCL 1 3 cells~ 0 4 nM [3H]spiperone defined by 1 /zM haloperidol: D42 (CHO K1 cells} 01 nM [3H]spiperone defined by 10 lzM halopendol; D5 (SF-9 cells) 15 riM SCH 23390 def ned by 1 #M (+)butaclamol Affinity constants (Kr nM; mean ± SEM) were determined using >_6 concentrations of displacing dr~g lrl 3 separate experiments) The results show tbat zotepine has high affinity for the humar D! D2,D 3 and D42 subtypes and moderate affinity for D 5 receptors Clozapine has lower affinities, but a similar spread of subtype affinity On the otter hand, haloperidol and rispendone have preferential affinities for D2-1ike receptors Cloned human dopamine receptor binding profiles D 1-like D1 D5 Zotepine 26±29 99±53 Clozapme 120±97 340±27 Haioperidol 96 J. 26 170 z 5 7 Rrsperidone 290±76 1230 = 180 Ki [nM); mean ± SEM; n 3

D2-1ike D2 12±20 210±27 3 1 :: 0 7 45+_05

D~ 31±05 180±!8 1 7 J- 0 1 34±07

D4 2 .89£08 31t:31 2 0 ~: 0 1 48 i:05

An imbalance in D! and D 2 receptor stimulation has been postulated to account forantipsychot~c-,nduced motor side-effects (Peacock, L e t a l , 1990). These data suggest that zotepine's reduced extrapyramidal sideeffect profile in humans derives, at least in oart. from balanced inhibition of D 1 like and D2-1ike receptors

References Muller, N-J and Moiler. WE (19941 Zotepme evaluation and possib~!ities for deve opment Nervenarzt,65 (Suppl), 2 4 Peacock. L , Lublin, H and Gerlach, J (1990} The effects of dopamine D1 and D2 receptor agonists and antagonists in monkeys withdrawn from long-term neuroleptpc treatment Eur J Pharmacol , 186, 49-59 Petit. M . Raniwalia, J , Leutenegger E , Tweed, JA and Kelly F (19951 A double blind study of zotepine vs haloperidol in schizophrenia (this meeting)

Seroquel": new pre-clinical research data confirm atypical antipsychotic actions Jeffrey M. GoldsteJn Department of CN$ Pharmaco/ogy, ZENECA Pharmaceutiea/s, 1800 Concord Pike, Wilmington. De~aware 19850-5437 SEROQUEL (IC[ 204,636), a dibenzoth~azepine with affinity for multiple brain receptors, is a potential atypicalantiDsychotic SEROQUEL is active in be havioral and electrophysiolog~c tests considered predictive of antipsychotic activity and satisfies the following pharmacologic criteria, which are putative predictors of atypicality: (1) a higher affinity for central 5-HT2A than D2 receptors; (2) limbic selectivity, as evidenced by depolarization inactivation of AIO but not A9 dopamine cells after chronic admiristration: (3) minimal dystonic liability in haloperidol sensitized and drug-naive cebus monkeys ~'4) transient elevations in prolactin after acute administration in rats. Newpre-clinicalresearchfirdngsfurtherdlstingu~shtheatypica antlpsy chotic profile of SEROQUEL

In squirrel monkeys trained to discriminate ctozapine from saline, SEROQUEL produced dose-dependent increases in response on the clozapine associated lever with full substitution at the highest doses tested. • In the prepulse inhibition (PPI) animal model of sensorimotor gating deficrts in schizophrenic patients, SEROQUEL restores PPI in apomorphinetreated rats with potency comparable to clozapine. Like clozapine but unlike haJoperidol, SEROQUEL also enhances PPh • Typical and atypical antipsychotics produce distinctly different induction patterns of neuronal Fos expression in the rodent forebrain. SEROQUEL like clozapine, selectively increases the number of neurons that displayed Fos-like immunoreactivity in the limbic-related nucleus accumbens and prefrontal cortex, but not in the motor related dorsolateral striatum, the site of activity for haloperidol-like agents. • In monkeys treated with amphetamine that exhibit asocial behavior, SEROQUEL not only reverses stereotypy, but restores social behavior. To the extent that this model mimics both the positive and negative symptoms of schizophrenia, SEROQU EL is predicted to exhibit enhanced antipsychotic efficacy • In the rat Paw Test (which discriminates between typical and atypical antipsychotics) SEROQUEL is more effective in prolonging hindlimb retraction time than forelimb retraction time, a profile also shared by clozapine. On the basis of the above results, SEROQUEL exhibits pharmacological properties that distinguish it as an atypical antipsychotic agent, not only with respect to clozapineqike minimal EPS liability, but perhaps enhanced antipsychotic efficacy. SEROQUEL'" is a trademark, the property of ZENECA Limited

The pre-clinical profile of the new antipsychotic ziprasidone R O'Connor, E. Harrigan. Pfizer Centre~Research, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK Ziprasidone is an investigational antipsychotic with a high 5HT2A/D2 ratio of antagonist activity, which predicts antipsychotic efficacy with reduced EPS compared with the classical antipsychotics. Additional effects on seroto~in and norepinephrine metabolism suggest the potential for efficacy in mood and anxiety symptoms. Low affinity for the alpha-1 and H1 receptors predict minimal problems with hypotension and sedation. Thus. the preclinical profile of ziprasidone, along with positron emission tomography studies in normal volunteers, support ziprasidone's potential as an effective antipsychotic with minimal side-effects Ziprasidone efficacy and tolerability have been evaluated in Phase II stud~es in comparison with haloperidol and placebo. Results of these trials support the conclusion that ziprasidone is an effective antipsychotic drug. when tested in patients experiencing an acute exacerbation of schizophrenia or schizoaffective disorder. Clinicat and laboratory evidence also suggests that ziprasidone is a remarkably well-tolerated drug in this patient population.

d-Amphetamine-induced abnormal behavior in the rat antagonized by SCH 23390 or raclopride P Salmi, TH. Svensson, S. Ahlenius. OepartmentofPhysio/ogyand Pharmacology, Karoh'nska Instituter, S- 171 77 Stockholm, Sweden The psychotomimetic compound d-amphetamine (AMPH) (4.0 mg kg -1) produces an abnormal behavior in the rat, as evidenced by a disruption of t~e discrimination of a visual stimulus (cue light vs no cue light), signalling which one of two passages (left or right) is required for a correct avoidance response in a shuttle-box. This disruption of discriminative behavior is fully restored by pretreatment with the unselective dopamine receptor blocking agent haloperidol (0.1 mg kg -1) The avoidance behavior per se is not affected by AMPH alone, or in combination with haloperidol. In order to further elucidate the relative role of dopamine (DA) D 1 and D2/D 3 receptor st,mulation for the effects of AMPH in this behavioral situation, the selective ~)A D1 and D2/D 3 receptor ligands (+)SCH-23390 (SCH) (0.02 mg kg -1) ancl raclopdde (RPD) (01 mg kg-1), respectively, were used as antagonists. Methods." Six adult male Wistar rats were trained in 10 daily sessions to perform a visual discriminative avoidance response as described above. The CS (white noise + cue light c o n d i t i o n s } - - USC (grid shock) interval was 10 s and correct and incorrect avoidance as well as escape responses were recorded. The animals served as their own controls and were given the d~fferent treatments subcutaneously: saline (2 ml kg-1), AMPH (4.0 mg kg-1), SCH {0.02 mg kg-1), RPD (0.1 mg kg-1), SCH + AMPH and RPD + AMPH Statistical analysis was performed with the Friedman two-