Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile

Ziprasidone is a novel antipsychotic agent with a unique combination of pharmacological activities at human receptors. Ziprasidone has high affinity for human 5-HT receptors and for human dopamine D(2) receptors. Ziprasidone is a 5-HT(1A) receptor agonist and an antagonist at 5-HT(2A), 5-HT(2C) and 5-HT(1B/1D) receptors. Additionally, ziprasidone inhibits neuronal uptake of 5-HT and norepinephrine comparable to the antidepressant imipramine. This unique pharmacological profile of ziprasidone may be related to its clinical effectiveness as a treatment for the positive, negative and affective symptoms of schizophrenia with a low propensity for extrapyramidal side effects, cognitive deficits and weight gain.     

Pharmacological actions of SM-9018, a new neuroleptic drug with both potent 5-hydroxytryptamine2 and dopamine2 antagonistic actions

Pharmacological studies were undertaken to clarify the profile of cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl) butyl) hexahydro-1H-isoindole-1,3-(2H)-dione hydrochloride (SM-9018), a new neuroleptic drug. SM-9018 had very high binding affinities for both 5-hydroxytryptamine2 (5-HT2) and dopamine2 (D2) receptors, unlike many other neuroleptics. SM-9018 also strongly inhibited 5-HT2 receptor-mediated behavior such as tryptamine-induced clonic seizure and D2 receptor-mediated behavior such as methamphetamine-induced hyperactivity, apomorphine-induced stereotypy and climbing behavior. SM-9018 possessed only a weak cataleptogenic activity, which may be clinically related to extrapyramidal side effects, despite its potent D2 antagonistic activity. Moreover, SM-9018 induced weak central depressant effects such as inhibition of spontaneous locomotor activity and motor coordination, as compared with classical neuroleptics (haloperidol and chlorpromazine). These results suggest that SM-9018 is a new neuroleptic drug with both potent 5-HT2 and D2 antagonistic activities and with low cataleptogenic and central depressant activities.     

Pharmacological profile of MS-377, a novel antipsychotic agent with selective affinity for σ receptors

Rationale: MS-377 ((R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone l-tartrate) was discovered as a new chemical entity with affinity for σ receptors and without affinities for dopamine receptors. Objective: In the present study, we examined the antipsychotic profile of MS-377 in several in vitro and in vivo experiments. Methods: As in vitro assays, radioligand binding assays for σ₁, σ₂, D₂ and 5-HT₂ receptors were performed. As in vivo animal models, the effects of MS-377 on several behavioral models induced by phencyclidine (PCP), (+)-N-allylnormetazocine (NANM), apomorphine (Apo) and 5-hydroxytryptamine (5-HTP) were evaluated. All assay systems were conducted using the clinically active antipsychotic agents as reference standards. Results: MS-377 displaced ligand bound to σ₁ receptors in vitro. However, no such displacement was observed at σ₂ or 5-HT₂ receptors in vitro, or at D₂ receptors either in vitro or in vivo. In behavioral studies, MS-377 inhibited both NANM- and PCP-induced head-weaving at low doses in mice and rats, whereas antipsychotic agents used in the present study were only effective against NANM- induced head-weaving behavior in mice. In addition, MS-377 antagonized Apo-induced climbing behavior and 5-HTP-induced head-twitching behavior in mice. MS-377 was inactive in models of extrapyramidal side effect (EPS) liability such as prevention of Apo-induced stereotypy and induction of catalepsy in rats. Conclusion: The present study demonstrated that MS-377 had not only anti-PCP activity but also anti-dopaminergic and anti-serotonergic activities in vivo, without acting directly through D₂ or 5-HT₂ receptors. Therefore, MS-377 could be a novel antipsychotic agent with clinical efficacy for overall symptoms of schizophrenia including its negative symptoms and without EPS liability. Received: 5 October 1998 / Final version: 22 January 1999     

Aripiprazole, a novel atypical antipsychotic drug

Before the 1990s, treatment of psychoses centered on conventional agents whose tolerability was limited by extrapyramidal side effects (EPS). The past decade has seen the emergence of a newer generation of antipsychotic agents, first with clozapine and followed shortly by risperidone, olanzapine, quetiapine, and ziprasidone. These agents have been touted as providing better negative symptom efficacy, less impaired cognition, and lower risk of extrapyramidal syndromes. However, evolving evidence suggests that several drugs in this class may be associated with significant weight gain and lipid abnormalities. Aripiprazole, a new atypical antipsychotic drug, displayed efficacy similar to that of haloperidol and risperidone and superior to that of placebo in numerous clinical trials. Aripiprazole does not cause significant prolactin elevation and is associated with a low rate of clinically significant weight gain compared with other atypical antipsychotics. Patients receiving aripiprazole experienced EPS at a rate similar to that seen with placebo. Aripiprazole provides a new treatment option with limited adverse effects for patients in need of antipsychotic therapy.     

新型抗精神病药：哌罗匹隆

哌罗匹隆是一种新型非典型抗精神病药,主要药理机制是5-羟色胺(5-HT)和多巴胺D_2受体拮抗作用。与传统抗精神病药相比,哌罗匹隆对阳性症状、阴性症状和情感症状均有较好疗效,锥体外系不良反应和致催乳素升高作用轻微。哌罗匹隆是一种安全有效的非典型抗精神病药。     

RMI-81,582, a novel antipsychotic drug

RMI-81,582 (2-chioro-11-3-dimethylaminopropylidene morphanthridene), a potential antipsychotic agent, was administered to eight chronic and four acute male schizophrenics in an open label study. Ten of twelve patients improved, particularly those who were experiencing their first hospitalization, regardless of whether they met Research Diagnostic Criteria for acute or chronic schizophrenia. Significant improvement was noted on the Clinical Global Impressions and Brief Psychiatric Rating Scale. No extrapyramidal side effects were noted and other adverse reactions were few. Serum prolactin levels, a measure of antidopaminergic activity, were increased by low-moderate dosages of RMI-81,582 in seven of eleven patients. Four patients had no increase in serum prolactin with RMI-81,582. In six of the seven patients who developed increases in serum prolactin, prolactin levels returned to those characteristic of the placebo period as the dosage of RMI-81,582 was increased. With classical neuroleptics, serum prolactin levels increase as the dose increases up to approximately the equivalent of chlorpromazine 600 mg/day and then remain fairly constant. The pattern of serum prolactin response in both man and laboratory animals and the absence of extrapyramidal side effects suggest RMI-81,582 may have a clozapine-like action.     

Binding and neuropharmacological profile of zaleplon, a novel nonbenzodiazepine sedative/hypnotic.

The binding properties of CL284,846 (zaleplon), a novel nonbenzodiazepine sedative/hypnotic, at benzodiazepine receptor subtypes were evaluated. Zaleplon was 14.3 times more potent at inhibiting [3H]flunitrazepam binding to membrane preparations of the cerebellum than to membrane preparations of the spinal cord. The gamma-aminobutyric acid (GABA) ratio of zaleplon was 2.07. Zaleplon produced significant increases in muscimol binding similar to those of diazepam, and it was antagonized by flumazenil. Furthermore, zaleplon showed little affinity for other receptors. Spectral analysis of the electroencephalogram (EEG) of rabbits showed that zaleplon and 3-methyl-6-[3-(trifluoromethyl) phenyl]-1,2,4,-triazolo [4,3-beta] pyridazine (CL218,872), an omega(1) receptor-selective compound (1 mg/kg, i.v., respectively), produced large increases in energy of the delta frequency band without affecting the energy of the alpha and beta frequency bands. In contrast, intravenous administration of triazolam and zopiclone increased the energy of the beta frequency band at doses of 0.1 and 2 mg/kg, respectively. In addition, the zaleplon-induced increase in the energy of the delta frequency band was antagonized by pretreatment with flumazenil (1 mg/kg, i.v.), which did not affect the spontaneous EEG alone. The present results clearly demonstrate that zaleplon is a selective full agonist of the omega(1) receptor subtype, and thus, zaleplon may induce responses closely resembling the physiological pattern of slow wave sleep.     

Pharmacological properties of SM-3997: a new anxioselective anxiolytic candidate

Pharmacological properties of SM-3997 (3a alpha,4 beta,7 beta,7a alpha-hexahydro-2-(4-(4-(2-pyrimidinyl)-1- piperazinyl)-butyl)-4,7-methano-1H-isoindole-1,3(2H)-dione dihydrogen citrate) have been examined in rats and mice. SM-3997 showed a dose-related anticonflict activity in rats in a water lick conflict paradigm, and it had no effect on water consumption in a spontaneous water drinking test. The potency of SM-3997 appeared to be equal to that of buspirone and about one-half that of diazepam. No tolerance to the anticonflict activity of SM-3997 was observed following 5 and 10 consecutive days of treatment. Unlike diazepam, SM-3997 had no anticonvulsant effect and had very weak muscle relaxant and hypnotic effects. On the other hand, SM-3997 and buspirone exhibited dopamine antagonistic action, although the potency of SM-3997 was less than one fourth that of buspirone. These results show that SM-3997 is a new anxioselective anxiolytic agent which is weaker than buspirone in the dopaminergic neuron system.     

非典型抗精神病药——哌罗匹隆

哌罗匹隆是一类非典型抗精神病药，疗效肯定，锥体外系反应等药物不良反应较少。本文就哌罗匹隆的药理作用、药代动力学特征及与其他药物的相互作用做一综述。     

BL-1020, a novel antipsychotic candidate with GABA-enhancing effects: D2 receptor occupancy study in humans

BL-1020 is a potentially novel antipsychotic, which comprises the typical antipsychotic perphenazine linked by an ester bound to γ-aminobutyric acid (GABA), intending a simultaneous dopamine-2 (D₂) receptor blockade and GABA facilitation in the brain. This positron emission tomography (PET) study, using [¹¹C]raclopride, assessed the extent and duration of D₂ receptor occupancy (D₂ RO) and safety for single doses of BL-1020 in healthy male subjects. Overall, this study did not raise any safety concern. Single doses of 16–32 mg BL-1020 caused a dose dependent striatal D₂ RO. The 32 mg dose of BL-1020 resulted in an average D₂ RO of 44% at 4–6 h post dosing (pd), which declined to 33% at 24 h pd. Equimolar doses of BL-1020 and perphenazine resulted in similar D₂ RO at 24 h pd. Pharmacokinetic–pharmacodynamic analysis predicted that oral once daily administration of 32 mg BL-1020 would result in D₂ ROs ranging from 52 to 66% at a steady state.     

Psychopharmacological profile of dapiprazole, a new potential antipsychotic agent

3-[2-[4-(2-Methylphenyl)-1-piperazinyl]ethyl]-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridine HCl (dapiprazole is a new compound endowed with a unique psychopharmacological profile. It inhibits amphetamine toxicity in grouped mice, and alcohol and morphine withdrawal syndromes, whereas it is almost inactive in the screening models for neuroleptics relying on dopaminergic activity. It also produces sedation, blocks conditioned avoidance reflex, reduces the response to noxious stimuli, has EEG synchronizing effects and inhibits the arousal reaction. Dapiprazole is a potent central and peripheral adrenolytic agent. Its acute toxicity is low. On the basis of these data, clinical investigations of dapiprazole are suggested in psychotic conditions such as the withdrawal syndromes, schizophrenia and schizo-affective disorders.     

EEG and behavioral profile of flutroline (CP-36,584), a novel antipsychotic drug

The pharmacologic profile of flutroline, a tetrahydro--carboline compound, predicts and antipsychotic compound with greater potency and longer duration than established clinical antipsychotic compounds. In normal male volunteers, it elicited EEG, behavioral, and plasma prolactin release profiles similar to established antipsychotic compounds. Peak activity occurred in 4–5 h. But the clinical activity projected from these studies is one-fifth that of haloperidol. In relation to the available clinical findings, the pharmaco-EEG data are better predictors of the clinical activity of flutroline than its preclinical profile.     

Pharmacological and biochemical assessment of SM-10888, a novel cholinesterase inhibitor

The effects of the compound SM-10888 (9-amino-8-fluoro-1,2,3,4-tetrahydro-2,4-methanoacridine citrate) in a number of pharmacological and biochemical tests were studied and compared to those of tacrine (THA), amiridin, HP-029 and physostigmine. SM-10888 inhibited cholinesterase activity (IC50: 2.3 x 10(-7) M) in rat cortical P2 fraction with almost the same potency as THA, while SM-10888 was 2-4 times more potent than amiridin and HP-029, but about 10 times less potent than physostigmine. When given to mice p.o., SM-10888 induced central (hypothermia) and peripheral (salivation) cholinergic effects. When the ratio of the ED50 value for hypothermia to that for salivation was regarded as the index of the selectivity to the central nervous system (CNS), SM-10888 was shown to be about 3 times more selective to the CNS than the other four drugs in mice. The minimum effective dose of SM-10888 for its increasing effect on acetylcholine (ACh) content in the mouse cerebral cortex was about 10 times higher than that of physostigmine, but 5-10 times lower than those of THA, amiridin and HP-029. These results suggest that SM-10888 is an adequate drug for increasing the brain ACh content with less peripheral cholinergic side effects than THA, amiridin, HP-029 and physostigmine.     

Lurasidone (SM-13496), a novel atypical antipsychotic drug, reverses MK-801-induced impairment of learning and memory in the rat passive-avoidance test

Lurasidone (SM-13496) is a novel atypical antipsychotic with high affinities to dopamine D2, serotonin 5-HT7, 5-HT2A, 5-HT1A receptors and alpha2C adrenoceptor. In this study, the effects of lurasidone on the rat passive-avoidance response and its impairment by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) were evaluated and compared with those of other antipsychotics. The passive-avoidance response was examined by measuring the step-through latency, 1 day after the animals received foot-shock training. When given before the training session, lurasidone did not affect the passive-avoidance response at any dose tested (1-30 mg/kg, p.o.). All the other atypical antipsychotics examined (i.e., risperidone, olanzapine, quetiapine, clozapine and aripiprazole), however, significantly reduced the step-through latency at relatively high doses. A pre-training administration of lurasidone significantly and dose-dependently reversed the MK-801-induced impairment of the passive-avoidance response. At doses lower than those that affected the passive-avoidance response, risperidone, quetiapine, and clozapine partially reduced the MK-801-induced impairment, whereas haloperidol, olanzapine, and aripiprazole were inactive. In addition, the post-training administration of lurasidone was as effective in countering the MK-801 effect as the pre-training administration, suggesting that lurasidone worked, at least in part, by restoring the memory consolidation process disrupted by MK-801. These results suggest that lurasidone is superior to other antipsychotics in improving the MK-801-induced memory impairment and may be clinically useful for treating cognitive impairments in schizophrenia.     

In vivo pharmacological profile of 9-hydroxyrisperidone,the major metabolite of the novel antipsychotic risperidone

9-Hydroxyrisperidone (9OH-risperidone) is the major metabolite of the new antipsychotic risperidone. 9OH-risperidone was compared with risperidone in a series of pharmacological tests in rats; ritanserin and haloperidol were included as reference compounds in tests for 5HT₂ and D₂ antagonism, respectively. 9OH-risperidone closely resembled risperidone and showed similar effects at closely related doses (respective subcutaneous [sc] ED₅₀s in mg/kg in parentheses): 5HT₂ antagonism: reversal of tryptamine cyanosis (0.00059/0.0011), inhibition and blockade of tryptamine seizures (0.032/0.014 and 0.11/0.056), inhibition of tryptamine tremors (0.34/0.049), inhibition and blockade of mescaline head twitches (0.056/0.037 and 0.098/0.049); D₂ antagonism: inhibition and blockade of apomorphine behavior (0.34/0.22 and 4.1/1.2), inhibition and blockade of amphetamine agitation (0.15/0.056 and 0.51/0.59) and oxygen consumption (0.049/0.016 and 0.17/0.64), behavioral disinhibition (0.069/0.31) and depression (4.6/4.7) in amphetaminized rats; histamine H₁ antagonism: protection from compound 48/80 lethality (0.018/0.014); α₁-adrenoceptor antagonism: protection from norepinephrine lethality (0.17/0.074); α₂-adrenoceptor antagonism: reversal of clonidine's antidiarrheal effect (0.29/0.67), reversal of xylazine loss of righting (16/2.4); and behavioral effects: slight and pronounced catalepsy (2.0/0.59 and 3.6/3.0), slight and pronounced palpebral ptosis (0.30/0.19 and 2.0/0.89), muscular hypotonia (4.7/3.6), hypothermia (4.1/2.0), inhibition of acetic acid writhing (1.2/0.34), and depression of motor activity (0.13/0.062 for vertical, 0.49/0.18 for horizontal, and 5.0/2.8 for total movements). Up to 10 mg/kg, both compounds were devoid of anti-muscarinic and anti-nicotinic activity, failed to affect the lethal effects of KCN, nitrogen, BaCl₂ and ouabain, and did not block castor oil diarrhea. The acute oral LD₅₀ values of the compounds were comparable. Both 9OH-risperidone and risperidone differed markedly from haloperidol as indicated by: (1) predominant central 5HT₂ antagonism (comparable to that of ritanserin); (2) high doses of catalepsy; (3) gradual depression of motor activity; (4) pronounced behavioral disinhibitory effects in amphetaminized rats; (5) inhibition of amphetamineinduced oxygen consumption preceding inhibition of amphetamine agitation. As metabolic conversion of risperidone to 9OH-risperidone does apparently not result in any marked change in activity profile, its major consequence seems to be a prolongation of duration of action. © 1994 Wiley-Liss, Inc.     

A novel carbapenem antibiotic, SM-7338 structure-activity relationships

A series of new carbapenem compounds, which have a pyrrolidin-3'-ylthio group substituted with various aminocarbonyl group at C-5' position as C-2 side chain, have been prepared. The antibacterial activity and the stability to renal dehydropeptidase-I of these compounds were investigated, and the structure-activity relationships were discussed. In this series, SM-7338; (1R,5S,6S)-2-[(3S,5S)-5-dimethylaminocarbonylpyrrolidin-3-ylthi o]-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid (5a) was the most interesting compound.     

In vitro study of a novel atypical beta-adrenoceptor agonist, SM-11044.

SM-11044 (L-threo-3-(3,4-dihydroxyphenyl)-N-[3-(4-fluorophenyl) propyl] serine pyrrolidine amide hydrobromide) stimulated the relaxation of guinea pig ileum (EC50: 3.0 x 10(-8) M), trachea (EC50: 1.3 x 10(-7) M), lung parenchyma (EC50: 2.1 x 10(-6) M) and the increase in right atrial rate (EC50: 6.9 x 10(-6) M). It also induced lipolysis of rat white adipocytes (EC50: 1.2 x 10(-6) M). Both the relaxant response of ileum and the lipolytic response of adipocytes to SM-11044 were resistant to inhibition by propranolol (10(-6) M), but were antagonized by cyanopindolol (10(-6) M). In contrast, the responses to SM-11044 in trachea, lung parenchyma and right atrium were almost completely abolished by propranolol (10(-6) M). Furthermore, the selectivity of SM-11044 relative to isoproterenol was ileum greater than adipocytes greater than trachea (beta 2) greater than lung (beta 2) greater than atrium (beta 1). These results suggest that SM-11044 is a selective agonist of atypical beta-adrenoceptors that are resistant to antagonism by propranolol but sensitive to cyanopindolol. The receptor binding and adenylate cyclase stimulating activity of SM-11044 were also examined on transfected Chinese hamster ovary cells expressing human beta 1-, beta 2- or beta 3-adrenoceptors. SM-11044 inhibited the binding of [125I]iodocyanopindolol to the three types of receptors in a concentration-dependent manner. The selectivity in terms of Ki values was beta 3 (Ki: 1.3 x 10(-6) M) greater than beta 2 (Ki: 4.1 x 10(-6) M) greater than beta 1 (Ki: 18.1 x 10(-6) M)-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological characteristics of perospirone hydrochloride, a novel antipsychotic agent

It is now known that the blockade of 5-HT2 receptors can ameliorate the negative symptoms of schizophrenia and extrapyramidal side effects (EPS) associated with antipsychotic treatments. Perospirone hydrochloride (perospirone), which was identified as a novel serotonin-dopamine antagonist (SDA)-type antipsychotic agent in 1987 by Sumitomo Pharmaceuticals, possesses high affinities both for dopamine 5-HT2 and D2 receptors. Perospirone, like conventional antipsychotics, significantly inhibited various behaviors induced by dopaminergic hyperactivation. Perospirone also produced a significant improvement in animal models of the negative symptoms and mood disorders, where the conventional antipsychotics were unaffected. In addition, perospirone was weaker than the conventional antipsychotics (e.g., haloperidol) in inducing EPS signs (e.g., catalepsy and bradykinesia), suggesting that the drug has an atypical antipsychotic property. A recent double-blind study with schizophrenia patients demonstrated that perospirone was comparative with haloperidol in improving the positive symptoms, but was significantly superior to haloperidol against the negative symptoms. Furthermore, the extrapyramidal score in patients with perospirone treatment was lower that those with haloperidol treatment. These findings suggested that perospirone acts as an antagonist both for 5-HT2 and D2 receptors and has broader clinical efficacy and lower EPS liability than haloperidol in schizophrenia treatment.     

Neuropharmacological profile of an atypical antipsychotic, NRA0562

Schizophrenia is a serious and disabling psychiatric disorder affecting approximately 1% of the world's population. A new generation of atypical antipsychotics has been introduced over the past decade. These atypical antipsychotics have comparable or greater efficacy than traditional antipsychotics in the treatment of the psychotic symptoms of schizophrenia and a much improved neurologic side effect profile. This paper reviews the pharmacological efficacy and safety of a potential atypical antipsychotic, NRA0562. NRA0562 has a high affinity for dopamine D1, D2L, D4.2, 5-HT2A receptors as well as alpha1-adrenoceptors, and has a moderate affinity for H1 receptors. NRA0562 strongly binds to 5-HT2A receptors and alpha1-adrenoceptors in the frontal cortex, its binding to striatal D2 receptors is weaker, similar to that of clozapine. NRA562 displayed potent antipsychotic activities in animal models of schizophrenia, such as methamphetamine (MAP)-induced hyperactivity, apomorphine-induced disruption of pre-pulse inhibition and conditioned avoidance test. NRA0562 is more potent in reversing the inhibitory effects of MAP at A10 than at A9 dopamine neurons. It increased Fos-like immunoreactivity in the nucleus accumbens more effectively than in the dorsolateral striatum, indicating that NRA0562 has the profile of an atypical antipsychotic. In vivo assays for extrapyramidal side effect liability showed that NRA0562 has a low rate of neurological side effects. Thus, NRA0562 may have unique antipsychotic activity with a lower propensity for extrapyramidal side effects.     

Seroquel: electrophysiological profile of a potential atypical antipsychotic

Extracellular single unit recording techniques were employed to compare the effects of seroquel with the reference antipsychotic (AP) agents clozapine and haloperidol in electrophysiological tests that may predict AP activity. Seroquel and clozapine were differentially more active in reversing the inhibitory actions ofd-amphetamine on mesolimbic (A10) than nigrostriatal (A9) dopamine (DA)-containing neurons, whereas haloperidol exhibited the opposite selectivity. In cell population studies, acute treatment with seroquel and clozapine selectively increased the number of spontaneously active A10 DA cells, which was found to correlate with the ability of both these drugs to cause depolarization inactivation (DI) of A10 DA cells following repeated (28 day) administration. This profile of activity was unlike that of haloperidol, which acutely caused a nonselective increase in the number of active A9 and A10 DA cells, associated with the ability of this agent to cause DI of both A9 and A10 DA cells after repeated treatment. Since DI of A10 DA cells may be correlated with AP efficacy whereas DI of A9 DA cells may predict the ability of an AP to cause extrapyramidal side effects (EPS) and tardive dyskinesia (TD), seroquel, like clozapine, may be an atypical AP with a reduced likelihood for producing EPS/TD.