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Background. The majority of those suffering from anxiety or related disorders are outpatients, and presumably involved in daily activities such as driving a car. However, anxiolytic drugs may possess sedative properties that reduce alertness and produce sleepiness. Therefore, it must be questioned whether it is safe to drive a car when treated with these drugs. Methods. A MEDLINE literature search (keywords driving and anxiety) and cross-references identified 14 placebo-controlled, double-blind studies that examined the effects of anxiolytic drugs on driving ability by conducting the on-the-road driving test during normal traffic. Primary parameter of the driving test is the Standard Deviation of Lateral Position (SDLP), the weaving of the car. Data from epidemiological studies was summarized as supportive evidence. Results. After single dose administration of benzodiazepines and related GABAergic compounds (diazepam, lorazepam, alprazolam, oxazepam, alpidem, suriclone, zolpidem) driving performance was significantly impaired. Further, although tolerance develops, driving studies show that the impairing effects of benzodiazepines and related GABAergic compounds may still be present after on week of daily treatment (demonstrated for diazepam, lorazepam, alpidem, suriclone). Driving performance was also significantly impaired after single dose administration of TCAs (imipramine, amitriptyline), but after repeated use of TCAs tolerance developed to the impairing effects on driving ability. In contrast, SSRIs (paroxetine, fluoxetine), venlafaxine, 5HT-antagonists (ritanserin, ondansetron) and buspirone produced no significant impairment on the driving test after both acute and repeated administration. These findings were in line with epidemiological evidence. Conclusions. Patients treated with benzodiazepines, GABAergic compounds, or TCAs should be cautioned when driving a car. Driving a car when treated with buspirone, venlafaxine, 5HT-antagonists, and SSRIs seems relatively safe.

Suriclone is a potent non-benzodiazepine anxiolytic belonging to the cyclopyrrolone family. This study examines the distribution and properties of [3H]-suriclone binding sites in rat brain by autoradiography. The binding of [3H]-suriclone to rat brain sections was displaced completely by 1 mM flumazenil; saturation experiments revealed a single class of binding sites with a KD value of 1.19 nM and a Bmax of 1.05 pmol/mg protein. The pharmacological specificity of [3H]-suriclone binding was close to that of the benzodiazepine binding site on the GABAA receptor. Unlike benzodiazepine (BZ) agonists, [3H]-suriclone binding to rat brain sections was not increased in the presence of GABA, and unlike imidazopyridines such as alpidem, suriclone was unable to discriminate between the BZ1 and BZ2 phenotype of the GABAA receptor. The autoradiographic distribution of [3H]-suriclone binding sites in the rat brain was heterogeneous and relatively similar to that previously described for GABAA receptors labelled by benzodiazepines; some regions, however, such as certain cortical areas, displayed a different labelling. The highest densities were found in frontal, occipital, parietal, and cingulate cortices (layers I, II, III, IV), in the molecular layer of the cerebellum, in the superior colliculus and in the hippocampus. Moderate binding densities appeared in numerous areas such as the inferior colliculus, the central grey, the dorsal raphe, and the hypothalamus whereas caudate putamen, globus pallidus, and thalamic nuclei displayed a low density of [3H]-suriclone binding sites. ©1995 Wiley-Liss, Inc.

Effects of benzodiazepine (diazepam, lorazepam) and benzodiazepine-like anxiolytics (alpidem, suriclone) and a 5-HT-3 antagonist (ondansetron) on actual driving performance were measured in three doub

Rats can be trained to discriminate benzodiazepines (BZ) from vehicle and there is considerable evidence that the stimulus effects of these drugs are mediated by activity atω (BZ) modulatory sites of the GABAA receptor complex. A number of recent studies, however, have indicated that differences may exist between the discriminative stimulus effects of benzodiazepines and those of certain non-benzodiazepine ligands for theω (BZ) receptors (e.g. zolpidem, abecarnil). As it is known that several subtypes ofω (BZ) sites are found in the central nervous system, and that drugs such as zolpidem have selectivity for certain subtypes, it is possible that differential stimulus effects may be associated with receptor selectivity. In the present study, correlations were calculated between the potencies of nine compounds with affinity forω receptors (diazepam, lorazepam, triazolam, clonazepam, alprazolam, zopiclone, suriclone, CL 218, 872 and zolpidem) to substitute for chlordiazepoxide in rats trained to discriminate a dose (5 mg/kg) of this benzodiazepine and the ability of the same compounds to inhibit the binding of [3H]-flumazenil from different structures in the rat central nervous system in vivo. The correlations obtained were: cerebellum 0.46, cortex 0.39, striatum 0.78 (P

A high-performance liquid chromatographic assay with diode-array detection has been developed for the toxicological screening of the newly developed non-benzodiazepine hypnotics and anxiolytics zopiclone, zolpidem, suriclone and alpidem. After single-step liquid-liquid extraction of plasma at pH 9.5 using chloroform-2-propanol-n-heptane (60:14:26, v/v), the substances are separated on a Nova-Pak C18 4-microns column (300 mm x 3.9 mm, I.D.), with methanol-tetrahydrofuran-pH 2.6 phosphate buffer (65:5:30, v/v) as the mobile phase (flow-rate 0.8 ml/min). Full ultraviolet spectra from 200 to 400 nm are recorded on-line during the entire analysis and may be automatically compared to spectra stored in a library. The retention times of the four drugs are 4.05 min (zopiclone), 4.66 min (zolpidem), 6.74 min (suriclone) and 10.97 min (alpidem). The analysis is performed in 15 min. The method is simple, rapid and highly specific. It is the first assay to be described for convenient screening of cyclopyrrolones and imidazopyridines.

Healthy elderly people aged 70 or more should receive a starting dosage of the anxiolytic drug suriclone half that recommended for younger people; frail or ill elderly people may require further dosage reduction. These conclusions were based on a study of the pharmacokinetics and tolerability of orally administered suriclone after a single dose of 0.2mg and after multiple doses of 0.2mg 3-times daily in 8 male and 8 female healthy elderly volunteers. Informal comparisons of the pharmacokinetic data from this study with studies in younger volunteers showed a 53% decrease in clearance and an 84% increase in elimination half-life. Area under the plasma concentration-time curve (AUC) for suriclone and total antigenic products in the elderly were twice the values in younger volunteers when adjusted for different dosage. There were no significant changes in pulse rate or blood pressure during the study. One person showed a change from sinus rhythm to atrial fibrillation. Six people had transient adverse events including unsteadiness, vomiting, difficulty in reaching for objects, urinary incontinence and sedation.

The objective of this article is to present an overview of new forms of psychotropic drug therapy that may be expected to play a role in psychiatric practice in the 1990s. In predicting these future developments, three lines of approach have been followed. Firstly, progress in elucidating basic neuronal mechanisms is described. The radioligand receptor binding technique has proved to be an especially powerful tool in the search for novel psychoactive compounds. Secondly, those mental health problems most likely to undergo intensive study are discussed. It is likely that special attention will be devoted to organic mental disorders related to aging (dementia) or chronic exposure to toxic substances. In addition, research will be aimed at explaining and reducing the occurrence of auto-aggressive and hetero-aggressive behaviour. Thirdly, the types of newly designed agents and treatment strategies currently under investigation are outlined. In particular, the development of pharmacological agents that interfere with serotonergic molecular mechanisms has opened the way to improving existing psychotropic drugs, to inventing drugs that achieve known clinical effects via different mechanisms of action, and even to discovering entirely new categories of psychotropic drugs.

Most of the currently used anxiolytic agents act via gaba or serotonin. The latter include drugs traditionally classified as antidepressants, which are reviewed in the next chapter. This chapter reviews the results of ten experimental studies investigating the effects of anxiolytics on driving performance using over-the-road tests. Results show that only the serotonergic drugs (buspirone, ondansetron and ritanserin) had a low potential for impairment. All gaba-agonists (diazepam, lorazepam, oxazepam, clorazepate, alprazolam, alpidem, suriclone) had moderate to severely impairing effects on driving in the doses studied. Impairment was clearly dose dependent, and increased on average with increasing blood concentrations. However, most studies analyzing correlations between drug concentrations in plasma and effects on driving performance found low and non-significant correlations, indicating that prediction of impairment from blood concentrations is problematic.furthermore, tolerance was found to develop only very slowly, and impairing effects did not seem to be counteracted by improvement in anxiety symptoms. Finally, subjects seemed relatively unaware of the effects of the drugs. Awareness of these effects was only seen with severe objective impairment, indicating that patients should be warned explicitly about the risks associated with using these drugs by their physicians or pharmacists.keywordswklv vwxgdvvrfldwhg zlwkohvv wkdqkljkhu wkdqlqglfdwhv wkdwthese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

The anxiolytic activity and tolerance of four doses of suriclone (0.1, 0.2, 0.3 and 0.4 mg tid), diazepam (5 mg tid), and placebo were compared in six parallel groups of 54-59 outpatients with generalized anxiety disorder (DSM III-R). After a 1-week placebo run-in period, the patients were treated for 4 weeks, with assessments at baseline and after 1, 2, and 4 weeks by the Hamilton anxiety scale and the Clinical Global Impressions. Results showed better improvement with active drugs as compared to placebo, without significant differences among the four different doses of suriclone and diazepam. The number of adverse events, particularly drowsiness, was significantly higher with diazepam than with suriclone, particularly 0.1 and 0.2 mg tid which did not differ from placebo. These results demonstrate that suriclone at daily doses ranging from 0.1 to 0.4 mg tid is an effective anxiolytic, better tolerated than diazepam.

1. 1. The behavioural effects of classical anxiolytics such as barbiturates and benzodiazepines have been well characterised. However, recent research has been aimed at the development of novel anxiolytics without problems of sedation, muscle relaxation, amnesia and dependence. 2. 2. A number of novel ω (benzodiazepine) receptor ligands with anxiolytic properties have been described including alpidem bretazenil, suriclone and abecarnil. Although these compounds share some behavioural effects with older anxiolytic drugs, such as increasing punished drinking, they also show many differences. Their novel profiles may be related to low intrinsic activity or to selectivity for ω receptor subtypes. 3. 3. The possibility that novel anxiolytics may be found among compounds active at serotonin receptors remains a strong hypothesis. Compounds, which, like buspirone, are active at 5HT 1A receptors may be anxiolytic as may be antagonists at 5HT 2 and 5HT 3 receptors. All these compounds have behavioural effects which differ from those of benzodiazepines. 4. 4. In order more effectively to screen for and develop novel anxiolytics it will be necessary to refine behavioural models in the light of feedback from the clinic.

1. In a double-blind, placebo-controlled sleep laboratory study single doses of suriclone, a new non-benzodiazepine anxiolytic binding to benzodiazepine receptors, were investigated with respect to sleep and awakening. 2. Sixteen healthy young volunteers spent 10 nights in the sleep laboratory: 1 adaptation night, 1 baseline night and 4 drug nights (placebo; 0.2 mg, 0.4 mg suriclone; 2 mg lorazepam as reference drug) and 4 subsequent wash-out nights (drug-interval: 1 week). Somnopolygraphic investigations (22.30 h to 06.00 h) were commenced 0.5 h after drug-intake. A self-rating scale for sleep and awakening quality as well as psychometric tests were completed in the morning. 3. Hypnotic effects were most pronounced after lorazepam in regard to total sleep time and sleep efficiency. After lorazepam as well as after 0.4 mg suriclone nocturnal awakenings decreased significantly as compared with placebo, which was reflected in an improved subjective sleep quality after both dosages. Suriclone 0.2 mg did not induce any alterations in all night sleep. 4. In the morning, well-being, drowsiness and reaction time performance deteriorated after lorazepam as compared with placebo but not after suriclone. The latter was significantly superior to lorazepam with respect to subjective awakening quality, well-being, emotional rapport, drowsiness and attention. 5. Blood pressure and pulse remained unchanged after all of the drugs. Critical flicker frequency and muscle strength decreased only after lorazepam as compared with placebo.

A series of benzodiazepine receptor ligands with different chemical structures were evaluated for their affinities at diazepam-sensitive and diazepam-insensitive binding sites for [ 3 H]Ro 15-4513 (ethyl-8-azido-5,60dihydro-5-methyl-6-oxo-4H-imidazo-[1,5a][1,4]benzodiazepine-3-carboxylate) in cerebellar GABA A receptors. Rats of Wistar strain and of alcohol-sensitive (ANT) and alcohol-insensitive (AT) lines were used. The ANT rats possess a single point mutation in their GABA A receptor α6 subunit, which makes their diazepam-insensitive sites sensitive to benzodiazepine agonists, unlike those of AT and Wistar rats. All compounds evaluated displayed high-affinity binding to diazepam-sensitive sites ( K i K i K i K i > 10000 nM). The oxoimidazoquinoxaline, 6-chloro-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-5-isopropyl-4-oxo-imidazol[1,5-a]quinoxaline (NNC 14-0578) and suriclone represent the first benzodiazepine receptor full agonists to bind with relatively high affinity ( K i ∼ 100 nM) to diazepam-insensitive sites. The 5 position substituted methoxybenzyl, dimethylallyl, and 4-fluorobenzyl oxoimidazoquinoxaline analogs demonstrated a 58–336-fold higher affinity for ANT than AT diazepam-insensitive sites. Classical benzodiazepines having a 5-phenyl substituent have demonstrated a similar preference for ANT sites, suggesting that all these structures bind to diazepam-insensitive sites in the same orientation. The other compounds evaluated demonstrated only a more modest selectivity (1–12-fold), indicating different structural requirements for binding to mutant ANT and wild-type AT and Wistar receptors. These results expand the range of ligands which display high affinity for diazepam-insensitive sites. Such compounds shoudl be helpful in determining intrinsic actions of high-affinity ligands at these sites and in assessing the contribution of these sites in enhanced sedative sensitivity of cerebellar function in the ANT rats.

In a double-blind, placebo-controlled, cross-over study, acute effects of suriclone — a cyclopyrrolone derivative — were investigated by means of topographic mapping of event-related potentials (ERPs). Fifteen normal volunteers, aged 22–35 years, received randomized, oral single doses of placebo, 0.1 mg, 0.2 mg and 0.4 mg suriclone and 1 mg alprazolam as a reference compound. ERPs were investigated in an auditory oddball paradigm before and 3 h after intake of each drug. In addition to 17 EEG leads, vertical and horizontal electro-oculograms (EOGs) were recorded. After EOG minimization and artifact identification, the peak latencies of the spatial average were determined by an automatic procedure. Compared to placebo, no significant effects of the low and middle doses of suriclone on N1 amplitude were observed; the highest dosage reduced N1 amplitude, as did 1 mg alprazolam to an even greater extent. While no consistent effects on P2 amplitude were observed after suriclone, alprazolam reduced P2 amplitude. P300 amplitude was reduced only after the highest dosage of suriclone, but much more so after alprazolam. P300 latency was not affected significantly by suriclone, but a marked prolongation of P300 latency was observed after 1 mg alprazolam. Concerning N1 and P2 effects, alprazolam, but not suriclone, may have an inhibitory influence on stimulus-induced cortical arousal. Concerning P300 effects, the used doses of suriclone were superior to 1 mg alprazolam, which seemed to have reduced cognitive information processing capacity and prolonged stimulus evaluation time. Self-rated well-being (adjective checklist) showed subtle beneficial effects after 0.1 mg and 0.2 mg, but marked sedative effects after both 0.4 mg suriclone and 1 mg alprazolam.

The effects of the cyclopyrrolones zopiclone and suriclone on the function of the central γ-aminobutyric acid type A (GABAAA) receptor complex in mouse brain were evaluated both in vitro and in vivo. Added in vitro to mouse cerebral cortical membranes, these compounds potently inhibited [3H]flumazenil binding with IC50 (50% inhibitory concentration) values of 35.8 nM (zopiclone) and 1.1 nM (suriclone). Similar results were obtained with cerebellar membranes, indicating that these drugs do not discriminate between putative type I and type II benzodiazepine receptors. The interaction of cyclopyrrolones with recognition sites present at the level of the GABA receptor complex appears to be competitive, because zopiclone decreased the affinity of the receptors for [3H]flumazenil without affecting the maximal number of binding sites. Moreover, zopiclone and suriclone did not affect the rate of dissociation of [3H]flumazenil from benzodiazepine receptors. The in vitro efficacy of zopiclone appeared different from that of suriclone and the benzodiazepines diazepam and flunitrazepam. Thus, zopiclone failed to affect muscimol-stimulated 36Cl− uptake and only slightly inhibited t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding. In contrast, like diazepam and flunitrazepam, suriclone increased muscimol-stimulated 36Cl− uptake and markedly inhibited [35S]TBPS binding. On the other hand, suriclone, like zopiclone, did not modify [3H]muscimol binding to mouse cerebral cortical membranes. Moreover, zopiclone antagonized the reduction in [35S]TBPS binding elicited by the benzodiazepine receptor full agonist diazepam. Consistent with its low efficacy in vitro, oral administration of zopiclone (2.5 to 100 mg/kg, p.o.) in mice failed to modify [35S]TBPS binding subsequently measured in cerebral cortical membranes “ex vivo”. In contrast, suriclone (10 to 20 mg/kg, p.o.), like diazepam, decreased [35S]TBPS binding measured ex vivo. Moreover, both zopiclone (50 to 100 mg/kg, p.o.) and suriclone (1 to 10 mg/kg, p.o.) abolished the increase in [35S]TBPS binding induced by isoniazid (200 mg/kg, s.c.). These results suggest that suriclone may enhance GABAergic transmission with an efficacy similar to that of diazepam. In contrast, the low efficacy of zopiclone both in vitro and in vivo suggests that this drug may act as a partial agonist at benzodiazepine receptors.

1. In a double-blind, placebo-controlled, cross-over study, acute pharmacokinetic, neurophysiological and psychotropic effects of suriclone, a new cyclopyrrolone derivative, were investigated and compared with alprazolam. 2. Fifteen normal young volunteers received randomized oral single doses of placebo, 0.1, 0.2 and 0.4 mg suriclone as well as 1 mg alprazolam as reference compound. Investigations were carried out before and 1, 2, 4, 6 and 8 h after drug administration. 3. Pharmacokinetic investigations by radioimmunoassay showed a dose-dependent fast rise of plasma concentrations with a peak at 1 h and a rapid decline thereafter. Both the Cmax and the AUC values exhibited a linear relationship to dose. 4. EEG brain mapping demonstrated significant CNS effects of both compounds, characteristic for tranquillizers (increase of beta, decrease of alpha and increase of delta activity; attenuation of total power and acceleration of the centroid, i.e. centre of gravity frequency). When compared with alprazolam, suriclone exerted less sedative effects. 5. Time-efficacy calculations showed the pharmacodynamic peak effect of suriclone from the 2nd to the 4th hour, and of alprazolam in the 1st hour. Dose-efficacy calculations showed that the most pronounced CNS changes occurred after 1 mg alprazolam, followed by 0.4, 0.2 and 0.1 mg suriclone. 6. Psychometric investigations demonstrated no significant effects after the two lower doses of suriclone, while 0.4 mg and 1 mg alprazolam induced a decrement both in noopsychic and thymopsychic variables seen after higher doses of anxiolytic sedatives. Psychophysiology (critical flicker fusion, pupillometry, and skin conductance measures) pulse rate, systolic and diastolic blood pressure remained unchanged. 7. Psychophysiology (critical flicker fusion, pupillometry and skin conductance measures) showed differential dose-dependent effects. Pulse rate, systolic and diastolic blood pressure remained unchanged. Anxiolytic-characteristic side-effects (tiredness, drowsiness, etc.) occurred predominantly after the highest doses 0.4 mg suriclone and 1 mg alprazolam.

Suriclone is a novel cyclopyrrolone exhibiting anxiolytic activity. Twelve healthy Caucasian male volunteers participated in the study. A single dose of suriclone 0.4 mg, imipramine 75 mg, suriclone 0.4 mg + imipramine 75 mg, or placebo was given according to a 4 x 4 Latin-square design in order to assess the effect of drug association on pharmacokinetics and psychomotor performances. Visual analogue scale ratings, critical flicker frequency, choice visual reaction time, and Pauli, picture memory and Sternberg tests were performed before and 1.5, 6 and 9 h after drug administration. Suriclone, with the exception of the Pauli test, had no effect on psychomotor performances. The imipramine-suriclone association appeared to disturb some performances (no statistical significance), probably due to the effect of imipramine. Blood samples were collected for determination of imipramine and suriclone plasma levels respectively by high-performance liquid chromatography and radioimmunoassays. Suriclone AUC, Cmax and Tmax were not affected by imipramine, and reciprocally.

Twelve healthy subjects received single oral doses of 0.4 mg suriclone (SU), 7.5 mg zopiclone (ZO) and placebo, alone and together with 50 mg chlorpromazine (CP), double blind and crossover, in Latin square order, at one-week intervals. Performance tests administered before and 1.5, 3.5 and 6 h after drug intake included digit symbol substitution and simulated driving combined in a "Global test", flicker fusion frequency, body balance and memory and subjective assessments. Changes from baseline were examined statistically. Performance and memory data were analysed from only 11 subjects. Compared to placebo, SU minimally affected "global" performance, although it slowed reactions and tended to impair digit substitution. ZO impaired "global" performance at 1.5 h, affected performance in several separate tests, and produced subjective muzziness. CP did not impair "global" performance, although it did impair digit substitution and render the subjects drowsy, weak and dreamy. The combinations SU + CP and ZO + CP definitely impaired "global" performance more than CP alone. This difference was also found in most objective tests but less so in the subjective tests. CP and its combinations produced similar increases in plasma prolactin. Active drugs and their combinations variably lowered blood pressure and increased heart rate, and one subject collapsed after CP. The treatments irregularly impaired spatial memory and learning acquisition. No pharmacokinetic interactions were seen in the plasma levels of suriclone, zopiclone and chlorpromazine. The impairment of performance after these combinations resembles that previously encountered after 2.5 mg lorazepam, or 15 mg diazepam + 100 mg remoxipride.

Alpidem in an imidazopyridine derivative which binds selectively to the omega 1 (BZ1) receptor subtype. It is active in some, but not all, behavioural tests sensitive to benzodiazepine anxiolytics and has clinical anti-anxiety effects. However, in a previous study, it was shown that alpidem did not substitute for chlordiazepoxide in rats trained to discriminate this benzodiazepine. The present experiments were carried out to investigate the discriminative stimulus properties of alpidem in greater detail. In the first experiment rats learned to discriminate a dose of 10 mg/kg alpidem from saline. Acquisition of the discrimination was long and performance unstable. Chlordiazepoxide, clorazepate and zolpidem substituted only partially for alpidem but the effects of the training dose of alpidem were blocked by 10 mg/kg flumazenil. The second experiment established stimulus control more rapidly to a dose of 30 mg/kg alpidem. Alpidem induced dose-related stimulus control, and dose-related and complete substitution for alpidem was produced by zolpidem, abecarnil, CL 218,872, triazolam and suriclone. Partial substitution occurred with chlordiazepoxide, clorazepate and pentobarbital. In most cases, high levels of substitution were produced only by doses which greatly reduced response rates even though the training dose of alpidem produced only modest decreases in rates. Ethanol, buspirone and bretazenil produced very little substitution for alpidem and both flumazenil and bretazenil antagonised the effects of alpidem. In two further experiments alpidem was found to substitute for the stimulus produced by zolpidem (2 mg/kg) but not for that produced by ethanol (1.5 g/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of the cyclopyrrolones suriclone and RP 59037 on body temperature were investigated in male TO mice. The full agonist suriclone (3, 10, 30 mg/kg i.p.) produced significant hypothermia which was inhibited by concurrent administration of benzodiazepine receptor antagonists of both benzodiazepine (flumazenil; 10 mg/kg i.p.) and beta-carboline (ZK 93426; 3 mg/kg i.p.) structure. The response to suriclone (10 mg/kg i.p.) was also attenuated by benzodiazepine (Ro 17-1812; 10 mg/kg i.p.) and beta-carboline (ZK 91296; 30 mg/kg i.p.) partial agonists - which have no effect on body temperature per se. In contrast with these compounds, the cyclopyrrolone partial agonist RP 59037 (10, 30 mg/kg i.p.) produced significant hypothermia itself (although it was much less efficacious in this respect than the full agonist) and at a dose of 30 mg/kg failed to block the decrease in body temperature induced by suriclone (10 mg/kg i.p.). Thus suriclone acts as a full agonist at benzodiazepine receptors in the body temperature paradigm. RP 59037 possesses some partial agonist properties in this model, however, it appears to have greater intrinsic activity than other partial agonists tested previously.

The objective of this article is to present an overview of new forms of psychotropic drug therapy that may be expected to play a role in psychiatric practice in the 1990s. In predicting these future developments, three lines of approach have been followed. Firstly, progress in elucidating basic neuronal mechanisms is described. The radioligand receptor binding technique has proved to be an especially powerful tool in the search for novel psychoactive compounds. Secondly, those mental health problems most likely to undergo intensive study are discussed. It is likely that special attention will be devoted to organic mental disorders related to aging (dementia) or chronic exposure to toxic substances. In addition, research will be aimed at explaining and reducing the occurrence of auto-aggressive and hetero-aggressive behaviour. Thirdly, the types of newly designed agents and treatment strategies currently under investigation are outlined. In particular, the development of pharmacological agents that interfere with serotonergic molecular mechanisms has opened the way to improving existing psychotropic drugs, to inventing drugs that achieve known clinical effects via different mechanisms of action, and even to discovering entirely new categories of psychotropic drugs.

Suriclone is a new anxiolytic drug belonging to the family of cyclopyrrolones. The effects of acute and repeated doses of suriclone on subjective sleep, psychomotor performance and cognitive function were compared to those of placebo in young and elderly volunteers. Young volunteers randomly received suriclone 0.2 mg, 0.3 mg, 0.4 mg or placebo tid, and the elderly received suriclone 0.1 mg, 0.2 mg or placebo tid. After the first single dose and after a three-day treatment, subjects completed at 1, 2, 4, 12 and 24 h after drug administration the following battery of psychomotor and cognitive tests: critical flicker fusion threshold, choice reaction time, simulated car tracking test, the stroop test and the Sternberg memory scanning task. Visual analogue scales and the Leeds sleep evaluation questionnaire were also administered during the study. No significant effects of suriclone compared to placebo were seen on the psychomotor tests both in young and elderly volunteers. The only significant result was an improvement of the ease of getting to sleep in the young with 0.4 mg suriclone tid. In conclusion, there is little evidence to suggest that suriclone produces any measurable behavioural toxicity, so often seen with many of the benzodiazepines, in either young or elderly subjects.

The effects of diazepam (5 mg t.i.d.), suriclone (0.2 and 0.4 mg t.i.d.) and placebo (t.i.d.) were assessed in 12 normal, healthy volunteer subjects after a single dose and after treatment for a period of 8 days. A battery of physiological, psychomotor and subjective tests was administered on days 1 and 8 both before and after drug and after a measured dose of ethanol. The effects of diazepam on the EEG were characteristic of benzodiazepines-a decrease in the slow frequency wave-bands, an increase in fast frequency wave-band and diminished evoked response amplitude. Suriclone had similar effects on fast frequency activity and evoked response amplitude but, in contrast to diazepam, also increased the slow frequency wave-bands after 7 days treatment. Some improvements in performance were seen with suriclone on critical flicker fusion, tapping speed, spiral maze and digit cancellation. In contrast, suriclone impaired performance to a greater extent than diazepam on digit symbol substitution and symbol copying. Body sway was also enhanced by suriclone to a greater extent than diazepam. Subjective ratings for mood and adverse-effects showed few differences between suriclone or diazepam. However, suriclone caused greater gastro-intestinal disturbances than diazepam, especially after ethanol, and subjects rated themselves as more antagonistic and more irritable on suriclone. Ratings for calmness suggested that in contrast to diazepam, suriclone had no anxiolytic effect. Several of the parameters tested showed a build up of effect with diazepam over the treatment period which was not seen with suriclone. It is suggested that this difference may be due to differences in elimination rate.(ABSTRACT TRUNCATED AT 250 WORDS)

In a model of physical dependence in mice, treatment with cyclopyrrolones such as zopiclone and suriclone (from 4 to 400 mg/kg/day), did not modify the sensitivity of the γ-aminobutyric acid (GABA) receptor complex to the partial inverse agonist FG 7142 following their withdrawal, whereas sensitivity changes were observed after treatment and withdrawal from some benzodiazepines (e.g. lorazepam, diazepam, flunitrazepam and triazolam). These data suggest that, in contrast to some benzodiazepines, zopiclone and suriclone may not produce physical dependence.

The interaction of suriclone and two of its main metabolites with central type benzodiazepine receptors, which had been labeled in vivo with the radioligand [11C]RO 15-1788, was investigated in living baboons. The concentration of radioligand bound to the receptors, as measured in brain transverse sections by positron emission tomography, decreased rapidly after the i.v. administration of suriclone at doses known to induce pharmacological effects. The rate and extent to which [11C]RO 15-1788 binding was displaced increased with increasing doses of suriclone. The half-inhibitory dose (ID50) was determined to be 0.08 mg/kg in vivo. The rapid inhibitory effect of suriclone on the in vivo binding of [11C]RO 15-1788 in the brain seems to reflect its ability to act at the GABA-benzodiazepine receptor complex, at or near to the benzodiazepine binding site, to induce its pharmacological activity. The i.v. injection of the demethylated metabolite of suriclone, RP 35,489, only caused a slight displacement of [11C]RO 15-1788 binding even at a dose of 2 mg/kg. Thus, suriclone appears to be more potent than RP 35,489 to displace the benzodiazepine 11C antagonist in vivo. The sulfoxide metabolite, RP 46,166, did not significantly change the kinetics of [11C]RO 15-1788 binding in the brain. The slight effects produced by high doses of RP 35,489 and RP 46,166 on [11C]RO 15-1788 binding in the brain suggest that these metabolites are probably not responsible for the expression of biological activity of suriclone mediated by benzodiazepine receptors.

In recent years a number of novel compounds have been described with affinity and specificity for BZ (ω) receptors While some of these agents appear to act. like benzodiazepines themselves, as full agonists ai different receptor subtypes (e.g. suriclone), several non -selective partial agonists (e.g

Rat hippocampus membranes were treated with several protein modifying reagents (iodoacetamide, N-ethylmaleimide, tetranitromethane and N-acetylimidazole). The effects of these treatments on the binding sites of cyclopyrrolones ([3H] suriclone), a new chemical family of minor tranquilizers, and benzodiazepines ([3H] flunitrazepam) were investigated. Here we show that both ligands are similarly sensitive to cysteine alkylation: [3H] suriclone and [3H] flunitrazepam binding are reduced by iodoacetamide and slightly increased by N-ethylmaleimide. On the contrary they are clearly differenciated by tyrosine modification: [3H] suriclone binding is not changed whereas [3H] flunitrazepam binding is increased by tetranitromethane and decreased by N-acetylimidazole. Our present findings and published evidence suggest cyclopyrrolones and benzodiazepines bind to distinct sites or to different allosteric forms of the benzodiazepine receptor.

Suriclone is a new anxiolytic drug belonging to the family of cyclopyrrolones. Chemically it is entirely different from the benzodiazepines, but it acts as a benzodiazepine agonist with very high affinity to a subgroup of benzodiazepine receptors or to a special conformation of these receptors. In the present cross-over study, 33 out-patients with a diagnosis of neurotic anxiety were treated with suriclone (mean dose 2 mg/day) and diazepam (25 mg/day) in two 6-week periods. Both drugs had a significant anxiolytic effect, but diazepam appeared to have a better effect within the first 2 weeks of treatment. On the other hand, the suriclone effect showed a tendency to increase over time in contrast to the effect of diazepam. Suriclone and diazepam had a different side effect profile: suriclone produced mainly dizziness, while diazepam caused sedation. It is suggested 1) that the observation of less anxiolytic effect of suriclone reflects the special affinity of this drug to a subgroup or a subconformation of ...

The action of suriclone (R.P. 31,264), a new non-benzodiazepine compound of the cyclopyrrolone family with clinical anxiolytic activity was examined using biochemical and electrophysiological models supposed to be capable of revealing central GABAergic activity. Suriclone, which does not act directly on the γ-aminobutyric acid (GABA) receptor (muscimol binding assay), markedly reduced the increase of striatal HVA level induced in the rat by a neuroleptic and decreased the cerebellar vermis cGMP content. Moreover, in the cat, suriclone was able to enhance dorsal root potential amplitude which reflects an increase of the presynaptic inhibition. In view of these results, a central GABAergic mechanism of action may be proposed for suriclone.

Suriclone, a nonbenzodiazepine drug, shown to be anxiolytic in animal pharmacology, was investigated within a single dose tolerance and efficacy study using quantitative pharmaco-EEG. The investigation showed that suriclone is tolerable in single oral doses of up to 0.8 mg, the highest dose given in healthy volunteers. The minimum effective dose producing statistically significant CNS action was 0.3 mg. Suriclone produced significant dose- and time-related CNS effects. The onset of these effects was later than that of diazepam and its duration of action was longer. Suriclone was classified by the HZI computer EEG drug data base as anxiolytic at high doses. Among a variety of anxiolytics, the CNS effect of suriclone was most similar to that of diazepam. The optimal anxiolytic effective single dose of suriclone was predicted to be 0.6 mg.

Up to now the only drugs known to be able to inhibit the binding of benzodiazepines to rodent brain receptors are members of this chemical family. Zopiclone (RP 27 267), a new drug with a pharmacological profile similar to that of chlordiazepoxide and nitrazepam but entirely different chemically from benzodiazepines, has been tested for its ability to inhibit benzodiazepine binding. In vitro and in vivo studies have shown that zopiclone is able to inhibit the binding of [3H] diazepam and [3H] flunitrazepam to brain receptors. The potency of zopiclone is quite comparable to that of diazepam and nitrazepam in vitro and to that of chlordiazepoxide in vivo . These results confirm the pharmacological similarities existing between zopiclone and the benzodiazepines.

Among the non-benzodiazepine compounds which have been found to interact with the “GABA receptor-BZ receptor-chloride channel complex,” the very chemically original cyclopyrrolone family has a special place. This has been demonstrated using selected pharmacological, biochemical and clinical data obtained with two cyclopyrrolones, zopiclone and suriclone, which, in addition to their capacity of displacing BZ from their sites, simultaneously possess the main pharmacological properties of BZ and well established therapeutic activities, as hypnotic and anxiolytic, respectively. However, although cyclopyrrolones recognize BZ receptor sites, their mechanism of action might not exactly fit with that of BZ. Indeed, using tritiated zopiclone and suriclone, it has been shown that they could act on sites distinct from those of BZ or could induce receptor conformational changes different from those induced by BZ.