Pharmacological and clinical studies of cyclopyrrolones: zopiclone and suriclone.

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.

Partial chemical characterization of cyclopyrrolones ([3H] suriclone) and benzodiazepines ([3H]flunitrazepam) binding site: differences.

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.

Suriclone, a new anxiolytic of the cyclopyrrolone family: evidence for possible interference with GABAergic systems.

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.

[Relation between the inhibitory effect on the synthesis of the rabbit aorta contracting substance and prostaglandins and the anti-inflammatory activity of ketoprofen and other non-steroidal anti-inflammatory agents].

This study showed that, relative to the other antiinflammatory drugs studied, ketoprofen is a stronger inhibitor of the synthesis of prostaglandins and Rabbit aorta Contracting Substance ("RCS") by guinea pig lung tissue in vitro. Although there seems to be no close correlation between their potency as inhibitors of prostaglandin synthesis and their effectiveness as antiinflammatory agents, evaluation of both activities results in classification of the drugs in the same order.

Suriclone: a new cyclopyrrolone derivative recognizing receptors labeled by benzodiazepines in rat hippocampus and cerebellum.

Suriclone (RP 31,264), like zopiclone (RP 27,267), belongs to the family of cyclopyrrolones and is chemically entirely different from the benzodiazepines (BZDs). However, it possesses a pharmacological profile close to that of the BZDs and proved to be useful in therapeutics as an anxiolytic agent. In the present paper it is shown that suriclone possesses a high affinity for flunitrazepam binding sites and that tritiated suriclone binds specifically with high affinity in rat hippocampus (KD = 0.

Brain receptors and zopiclone.

Zopiclone (ZPC; RP 27,267), which is chemically unrelated to benzodiazepines (BZD), was found to have a similar pharmacological profile and to possess in man hypnotic activity similar to that of some BZD such as nitrazepam. It was, therefore, interesting to study the interaction of ZPC with rat brain receptors and specially with the so-called 'BZD receptors'. ZPC possesses in three rat brain regions a high affinity for BZD receptors: its Ki values measured against [3H]-flunitrazepam are 24 nM in the cerebral cortex, 31 nM in the cerebellum, and 36 nM in the hippocampus.

Pharmacological studies on zopiclone.

Zopiclone (RP 27 267) is an hypnotic with a chemical structure different from that of the benzodiazepines (BZD) or barbiturates. Studies of zopiclone in classical psychopharmacological tests, in comparison with BZD and barbiturates, have shown that it exhibits the five main types of activity considered as characteristic of the pharmacological profile of BZD and partly of that of barbiturates (anticonvulsant, myorelaxant, antiaggressive, sedative-hypnotic and 'anticonflict'). However, like BZD, zopiclone differs from barbiturates by a high safety margin.

Brain receptors and zopiclone.

Zopiclone (ZPC; RP 27,267), which is chemically unrelated to benzodiazepines (BZD), was found to have a similar pharmacological profile and to possess in man hypnotic activity similar to that of some BZD such as nitrazepam. It was, therefore, interesting to study the interaction of ZPC with rat brain receptors and specially with the so-called 'BZD receptors'. ZPC possesses in three rat brain regions a high affinity for BZD receptors: its Ki values measured against [3H]-flunitrazepam are 24 nM in the cerebral cortex, 31 nM in the cerebellum, and 36 nM in the hippocampus.

Pharmacological studies on zopiclone.

Zopiclone (RP 27 267) is an hypnotic with a chemical structure different from that of the benzodiazepines (BZD) or barbiturates. Studies of zopiclone in classical psycho-pharmacological tests, in comparison with BZD and barbiturates, have shown that it exhibits the five main types of activity considered as characteristic of the pharmacological profile of BZD and partly of that of barbiturates (anticonvulsant, myorelaxant, antiaggressive, sedative-hypnotic and 'anticonflict'). However, like BZD, zopiclone differs from barbiturates by a high safety margin.

[Antiarrhythmic properties of 3-(2-hydroxy-3 isopropylamino-propoxy)-3 phenyl-2 isoindolinone-1, (RS, SR) in the dog].

In the Dog, 3-(2-hydroxy-3 isopropylamino-proxy)-2-phenyl-1-isoindolinone (RS, SR) possesses an anti-arrhythmic activity similar to that of quinidine but at dose levels 2 to 6 times lower than in the case of the latter compound. Furthermore, in contrast to quinidine, at the dose levels where the antiarrhythmic activity is well observed, the compound is devoid of hypotensive activity and of depressive action on cardiac contractility. The first clinical studies of this compound have shown its usefulness in the treatment of ventricular and supraventricular arrhythmias.

Some pharmacological and toxicological studies on ketoprofen.

Evidence for the effectiveness of ketoprofen in animal models of inflammation and its antipyretic effect is reviewed. Its toxicity in animals is discussed and the low tendency to produce ulcers is stressed.

Relationship between the inhibitory activity on 'RCS' and prostaglandins synthesis and the anti-inflammatory activity of ketoprofen and several other non-steroidal anti-inflammatory agents.

In this study ketoprofen has been shown to be the most potent of all anti-inflammatory drugs in inhibiting the synthesis of prostaglandins and the 'rabbit-aorta contracting substance' (RCS), using the guinea-pig lung preparation. Although there did not appear to be a close relationship between the activities of the various drugs in inhibiting prostaglandins synthesis and in their anti-inflammatory activity, the compounds were ranked in the same order in both test systems.

Ketoprofen (19.583 R.P.) (2-(3-benzoylphenyl)-propionic acid). Main pharmacological properties--outline of toxicological and pharmacokinetic data.

Ketoprofen possesses the typical pharmacological properties of non-steroidal anti-inflammatory agents i.e. anti-inflammatory, analgesic and antipyretic activity, as well as antibradykinin activity and ability to inhibit prostaglandin synthesis.

Acute and subacute effects of neuroleptics dopamine synthesis and release in the rat striatum.

The effects of acute and subacute treatments with moderate doses of thioproperazine and haloperidol on dopamine synthesis and release have been examined in rat striatal slices. Synthesis and release of dopamine were determined by measuring the rate of formation of 3H-H2O during the conversion of L3,5-3H-tyrosine into 3H-Dopa and the accumulation of newly synthesized 3H-dopamine in striatal slices and their incubating medium. Possible effects of the treatments on tyrosine striatal levels or tyrosine specific activity were also investigated.