Comparison of the effects of zaleplon,zolpidem, and triazolam at various GABA(A) receptor subtypes

The pyrazolopyrimidine zaleplon is a hypnotic agent that acts at the benzodiazepine recognition site of GABA(A) receptors. Zaleplon, like the hypnotic agent zolpidem but unlike classical benzodiazepines, exhibits preferential affinity for type I benzodiazepine (BZ(1)/omega(1)) receptors in binding assays. The modulatory action of zaleplon at GABA(A) receptors has now been compared with those of zolpidem and the triazolobenzodiazepine triazolam. Zaleplon potentiated GABA-evoked Cl(-) currents in Xenopus oocytes expressing human GABA(A) receptor subunits with a potency that was higher at alpha1beta2gamma2 receptors than at alpha2- or alpha3-containing receptors. Zolpidem, but not triazolam, also exhibited selectivity for alpha1-containing receptors. However, the potency of zaleplon at these various receptors was one-third to one-half that of zolpidem. Zaleplon and zolpidem also differed in their actions at receptors containing the alpha5 or gamma3 subunit. Zaleplon, zolpidem, and triazolam exhibited similar patterns of efficacy among the different receptor subtypes. The affinities of zaleplon for [(3)H]flunitrazepam or t-[(35)S]butylbicyclophosphorothionate ([(35)S]TBPS) binding sites in rat brain membranes were lower than those of zolpidem or triazolam. Furthermore, zaleplon, unlike zolpidem, exhibited virtually no affinity for the peripheral type of benzodiazepine receptor.     

Differences in pharmacological profiles of a new generation of benzodiazepine and non-benzodiazepine hypnotics

The hypnotics, quazepam (a benzodiazepine), brotizolam (a thienotriazolodiazepine), zopiclone (a cyclopyrrolone) and zolpidem (an imidazopyridine) have a common ability to bind to the benzodiazepine recognition site (omega receptor) within the GABAA receptor. For this reason we compared their pharmacological profiles in mice. All compounds shared anticonvulsant and central depressant effects. However, the sedative activity of zolpidem appeared at much lower doses than did the anticonvulsant and myorelaxant effects but the opposite was observed with the other hypnotics. In contrast to brotizolam, quazepam and zopiclone, zolpidem did not increase food intake in mice placed in a novel environment, indicating that this drug lacks disinhibitory activity. Moreover the efficacy of zolpidem at the GABAA receptor, as indicated by its activity against convulsions induced by the GABA synthesis inhibitor, isoniazid, was much greater than that of other hypnotics. These results suggest that the hypnoselective properties observed with zolpidem might be related to a high selectivity for the omega 1 recognition site of the GABAA receptor coupled with a very high intrinsic activity.     

The pharmacology and mechanisms of action of new generation, non-benzodiazepine hypnotic agents

The new generation hypnotic drugs, zolpidem, zopiclone and zaleplon, are at least as efficacious in the clinic as benzodiazepines and may offer advantages in terms of safety. These drugs act through the BZ binding sites associated with GABAA receptors, but show some differences from benzodiazepines in pharmacological effects and mechanisms of action. Of particular interest is the finding that zolpidem shows a wide separation between doses producing sedative effects and those giving rise to other behavioural actions, and induces less tolerance and dependence than benzodiazepines. Zolpidem also demonstrates selectivity for GABAA receptors containing alpha1 subunits. Recent studies using genetically modified mice have confirmed that receptors containing alpha1 subunits play a particularly important role in mediating sedative activity, thus providing an explanation for the pharmacological profile of zolpidem.     

Interaction of the hypnotic lormetazepam with central benzodiazepine receptor subtypes omega 1, omega 2 and omega 3]

To clarify the action of lormetazepam, 3-hydroxybenzodiazepine, on the benzodiazepine (BZ) receptor subtypes, effects of lormetazepam on motor performance in the traction test and hexobarbital-induced loss of righting reflex in mice and the binding to BZ receptor subtypes were investigated in comparison with those of other BZ hypnotics. Lormetazepam prolonged the duration of hexobarbital-induced loss of righting reflex. The minimal effective dose (1 mg/kg, p.o.) was higher than that of flunitrazepam, lower than those of diazepam and zopiclone, and the same as those of triazolam and brotizolam. Lormetazepam showed the ataxic effect at 10 mg/kg, p.o., but the separation between its effective doses for the hypnotic and ataxic effects was the largest among the hypnotics tested. In the displacement study on [3H]flumazenil binding to cerebellar and spinal cord membranes, lormetazepam bound with a higher affinity to omega 1 receptor (Ki = 10 nM) than to omega 2 receptor (Ki = 29 nM). The GABA-ratios of lormetazepam to omega 1 and omega 2 receptors were 3.9 and 4.0, respectively; and they were higher and lower than those of flunitrazepam to omega 1 and omega 2 receptors, respectively. In the displacement study on [3H] Ro5-4864 binding to kidney membranes, lormetazepam bound with a lower affinity to the omega 3 receptor (Ki = 213 nM) than flunitrazepam. Thus, lormetazepam was suggested to be a potent hypnotic with weaker ataxic effects than other BZ hypnotics, which may be due to its selective and potent agonistic action on central omega 1 receptors.     

Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes]

We examined the behavioral pharmacological properties of six benzodiazepine (omega) receptor ligands including brotizoram, nitrazepam, quazepam, rilmazafone, zolpidem and zopiclone and the binding of these drugs with omega receptor subtypes. Behavioral tests were performed at the time of the maximal effects induced by each drug following its oral administration to mice. All of these drugs dose-dependently induced impairment of motor coordination as rotarod performance and potentiation of thiopental-induced anesthesia as hypnotic effect. The hypnotic effects of rilmazafone, whose major metabolites were bound to both omega1 and omega2 receptors with high affinity, and omega1 selective quazepam were about 20 times more effective than the induction of motor impairments when compared with ED50 values. However, there was no difference between the ED50 values of omega1 selective zolpidem alone in these two tests. An antianxiety efficacy of zolpidem was relatively weak unlike that of other drugs in the elevated plus-maze. It has been reported that omega2, but not omega1, receptors are associated with motor impairment and anxiolytic effect. The weak anxiolytic effect of zolpidem supports the previous hypothesis. However, the strong motor incoordination of zolpidem suggests that not only omega2 but also omega1 receptors are related to motor impairment unlike the previous hypothesis.     

GABAA receptor complex function in frontal cortex membranes from control and neurological patients.

The functional integrity of the GABAA receptor-benzodiazepine (BZ) recognition site-Cl- ionophore complex was assessed by means of [35S]TBPS (t-butylbicyclophosphorothionate) binding to frontal cortex membranes prepared from frozen postmortem brain tissue taken from control (n = 4), Alzheimer (n = 7), Parkinson (n = 3) and Huntington's chorea (n = 2) patients. Specific [35S]TBPS binding was similar in control, Parkinson's disease and Huntington's chorea brains, but was significantly reduced (78% control, P less than 0.01) in frontal cortex membranes from Alzheimer's patients. The linkage between the BZ recognition sites and the GABAA receptor-linked Cl- ionophore was functionally intact in these membranes as BZ site agonists (zolpidem, alpidem, flunitrazepam and clonazepam) enhanced [35S]TBPS binding under the conditions used (well-washed membranes in the presence of 1.0 M NaCl). Zolpidem (BZ1 selective) exhibited a biphasic enhancement in control membranes whereas the other compounds induced a bell-shaped concentration-response curve. The enhancement of [35S]TBPS binding by alpidem, flunitrazepam and clonazepam was greater in frontal cortex membranes from Alzheimer's patients than in controls whereas it tended to be reduced in membranes from the brains of Huntington's chorea patients. These studies demonstrate the functional integrity of the GABAA receptor macromolecular complex and also the usefulness of [35S]TBPS binding in the study of human postmortem tissue.     

Selective effects of zolpidem on human memory functions

Zolpidem is an imidazopyridine hypnotic with preferential binding affinity for the omega1-benzodiazepine (BZD) receptor. The present double-blind, placebo-controlled study evaluated the effects of orally administered zolpidem (15mg/70kg) on specific memory functions in 16 healthy volunteers using a battery of word and picture memory tasks. Relative to placebo, zolpidem significantly impaired memory for material presented after drug administration when memory was assessed directly by referring subjects back to the prior study episode (explicit memory: recall and recognition) but not when memory was assessed indirectly by evaluating subjects' ability to identify degraded versions of studied stimuli (implicit memory: fragment completion). Zolpidem did not impair explicit memory for material presented before drug administration or memory for previously acquired knowledge (semantic memory: categorization). There was evidence suggesting that zolpidem enhanced explicit and implicit memory for material presented before drug administration and that zolpidem produced a specific deficit in the acquisition of contextual information about material presented after drug administration. Despite zolpidem's unique pharmacological profile, the observed selectivity of zolpidem's memory-impairing effects for particular functions appears qualitatively similar to the selectivity observed with classic BZDs in previous studies.     

The interaction between zolpidem and beta-CMC: a clue to the identification of receptor sites involved in the sedative effect of zolpidem

The interaction of beta-CMC, an amino beta-carboline recently described as a selective antagonist of the sedative effect of diazepam, with zolpidem, an imidazopyridine hypnotic, which like beta-CMC binds preferentially to the omega 1 (BZ-1) site of the GABA benzodiazepine chloride channel receptor complex, was investigated. In mice, beta-CMC antagonized the effect of zolpidem against isoniazid-induced convulsions without affecting its activity against convulsions induced by pentylenetetrazole or electroshock. beta-CMC also antagonized the decrease in locomotor activity and the impairment in muscle strength provoked by zolpidem. In rats trained to discriminate zolpidem, beta-CMC antagonized both the interoceptive stimulus and the decrease in the rate of lever pressing produced by zolpidem. This selective antagonism, inhibition of effects of zolpidem exerted by low doses (locomotor activity and isoniazid-induced convulsions) as well as effects produced by high doses (muscle strength) but not those provoked by intermediate doses (pentylenetetrazole and electroshock-induced convulsions), could not be explained by a receptor occupancy hypothesis. These results suggest that the anticonvulsant and sedative effects of zolpidem do not involve the same receptor subtype and that the hypnoselective properties of zolpidem may be linked to its selectivity for the omega 1 (BZ-1) site of the GABAA receptor.     

Enhancement of GABAergic transmission by zolpidem, an imidazopyridine with preferential affinity for type I benzodiazepine receptors

The effect of zolpidem, an imidazopyridine derivative with high affinity at the type I benzodiazepine recognition site, on the function of the GABAA/ionophore receptor complex was studied in vitro. Zolpidem, mimicking the action of diazepam, increased [3H]GABA binding, enhanced muscimol-stimulated 36Cl- uptake and reduced [35S]TBPS binding in rat cortical membrane preparations. Zolpidem was less effective than diazepam on the above parameters. Zolpidem induced a lower increase of [3H]GABA binding (23 vs. 35%) and muscimol-stimulated 36Cl- uptake (22 vs. 40%) and a smaller decrease of [35S]TBPS binding (47 vs. 77%) than diazepam. The finding that zolpidem enhanced the function of GABAergic synapses with an efficacy qualitatively and quantitatively different from that of diazepam suggests that this compound is a partial agonist at the benzodiazepine recognition site. Thus, our results are consistent with the view that the biochemical and pharmacological profile of a benzodiazepine recognition site ligand reflects its efficacy to enhance GABAergic transmission. Whether the preferential affinity of zolpidem at the type I site is involved in its atypical biochemical and pharmacological profile remains to be clarified.     

Chlormethiazole: neurochemical actions at the gamma-aminobutyric acid receptor complex

Chlormethiazole has been extensively employed as a sedative/hypnotic and anticonvulsant for more than 25 years. While pharmacological and electrophysiological studies have implicated the GABAA receptor complex in these actions, neurochemical findings have not been consistent with this conclusion. We now present evidence that pharmacologically relevant concentrations of chlormethiazole perturb the GABAA receptor complex. Chlormethiazole was found to increase 36Cl- uptake into rat cortical synaptoneurosomes in a concentration-dependent (EC50 = 48 +/- 3 microM; Emax = 8.9 +/- 0.8 nmol Cl-/mg protein per 5 s), picrotoxin-sensitive fashion. Chlormethiazole was also found to inhibit the binding of the 'cage' convulsant [35S]t-butylbicyclophosphorothionate to rat cortical membranes (IC50 = 58.6 +/- 0.6 microM) through an increase in the apparent KD of this radioligand. Moreover, at these concentrations chlormethiazole did not affect pentobarbital-enhanced [3H]flunitrazepam binding, but inhibited [3H]flunitrazepam binding with a low potency (IC50 = 1.6 +/- 0.2 mM). These findings provide neurochemical evidence that pharmacologically relevant concentrations of chlormethiazole can perturb the GABAA receptor complex, and suggest that this compound acts at a distinct locus from other sedative/hypnotics such as barbiturates, benzodiazepines and GABAmimetics.     

Pharmacological profile and clinical effect of zolpidem (Myslee tablets), a hypnotic agent

Zolpidem is a non-benzodiazepine hypnotic agent with a chemical structure of imidazopyridine. In vitro and in vivo binding studies, zolpidem exhibits selectivity to omega 1 receptors (GABAA-receptor subtypes containing alpha 1 subunits). Unlike benzodiazepines, zolpidem produces sedative effects in preference to anxiolytic, anticonvulsant and myorelaxant effects in behavioral experiments using mice. Double-blind comparative studies with reference drugs such as triazolam and zopiclone show that zolpidem is an effective and highly safe drug for the treatment of insomnia. In addition, zolpidem does not produce next-day residual effects, rebound insomnia and tolerance. This clinical profile of zolpidem may be related to its selectivity and high intrinsic activity for omega 1 receptors.     

Regional differences in the inhibition of mouse in vivo [3H]Ro 15-1788 binding reflect selectivity for alpha 1 versus alpha 2 and alpha 3 subunit-containing GABAA receptors.

The benzodiazepines flunitrazepam, diazepam, and Ro 15-1788 and the beta-carboline DMCM bind with equivalent affinity to the benzodiazepine binding site of GABAA receptors containing different alpha subunits (i.e., alpha 1, alpha 2, alpha 3, or alpha 5); whereas, the triazolopyridazine CL 218,872 and imidazopyridine zolpidem have higher affinity for alpha 1 subunit-containing GABAA receptors. In the present study, the in vivo binding of [3H]Ro 15-1788 in mouse cerebellum and spinal cord was used to establish the occupancy of the benzodiazepine binding site of GABAA receptors containing primarily alpha 1 and alpha 2/alpha 3 subunits, respectively. Thus, the nonselective compounds flunitrazepam, diazepam, and DMCM all produced a similar inhibition of binding in cerebellum and spinal cord (respective ID50 values of 0.2 to 0.3 mg/kg, 2 mg/kg, and 10 mg/kg i.p.); whereas, the alpha 1 selective compounds CL 218,872 and zolpidem were more potent at inhibiting [3H]Ro 15-1788 binding in the cerebellum (ID50 values 4.5 mg/kg and 10 mg/kg i.p.) compared to the spinal cord (ID50 values 12 mg/kg and > 30 mg/kg i.p.). Thus, the reduction of in vivo f[3H]Ro 15-1788 binding in tissues containing alpha 1 and alpha 2/alpha 3 receptor populations reflects the in vitro affinities of subtype selective compounds and should help to interpret the behavioral profile of such compounds.     

Chronic agonist exposure induces down-regulation and allosteric uncoupling of the gamma-aminobutyric acid/benzodiazepine receptor complex

Using [3H]flunitrazepam as a probe for the benzodiazepine-sensitive modulator site located on the gamma-aminobutyric acid (GABA)A receptor complex, we have investigated the cellular regulation of the GABAA receptor in neuronal cultures derived from embryonic chick brain. Treatment of cultures with 1 mM GABA for 48 hr causes a reversible 35% decrease in the number of [3H]flunitrazepam binding sites with no change in affinity. The EC50 for chronic GABA-induced down-regulation is 94 microM and the half-time is 25 hr. The effect of GABA is blocked by SR-95531, a GABAA receptor antagonist, and mimicked by muscimol but not baclofen. Consistent with the decrease in [3H]flunitrazepam binding, chronic GABA exposure causes a 43% decrease in the binding of [35S]t-butylbicyclophosphorothionate, a ligand for the receptor-associated chloride ionophore. In addition to chronic GABA-induced down-regulation, allosteric interactions between GABA and benzodiazepine recognition sites are uncoupled by 34%. The half-time and pharmacology for chronic GABA-induced uncoupling is indistinguishable from that for GABA-induced down-regulation, consistent with the hypothesis that the action of GABA at a common site induces both down-regulation and uncoupling.     

The effect of ethanol on 35S-TBPS binding to mouse brain membranes in the presence of chloride

The effect of in vitro and in vivo administration of ethanol on the binding of 35S-t-butyl-bicyclophosphorothionate (35S-TBPS) to cortical brain membranes of C57Bl mice was investigated using KCl (100 mM) containing assay media. The in vitro addition of ethanol produced a dose-dependent inhibition of basal 35S-TBPS binding. In the presence of chloride ions, GABA and pentobarbital had a biphasic action (stimulation followed by inhibition) on 35S-TBPS binding, whereas diazepam only stimulated the binding. Ethanol reduced the stimulatory effects of GABA and pentobarbital in a dose-dependent manner, but had no effect on the enhancement of 35S-TBPS binding produced by diazepam. 35S-TBPS binding to cortical brain membranes was inhibited by the putative Cl- channel blocking agent DIDS. This inhibitory action of DIDS was significantly, and dose-dependently reduced by ethanol (greater than or equal to 100 mM ethanol). Chronic ethanol ingestion in vivo, which produced tolerance to and physical dependence on ethanol in the animals, did not alter the stimulatory and inhibitory effects of GABA and pentobarbital on 35S-TBPS binding. The enhancement of 35S-TBPS binding produced by diazepam was slightly, but significantly, enhanced in brain membranes from animals which had undergone 24 hours of ethanol withdrawal. Chronic ethanol treatment did not change the potency of picrotoxin and of the peripheral BDZ-receptor ligand RO 5-4864 to competitively inhibit 35S-TBPS binding. Our results suggest that in vitro addition of ethanol alters the activity of the GABA/benzodiazepine (BDZ) receptor complex.(ABSTRACT TRUNCATED AT 250 WORDS)     

Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia

Zolpidem is an imidazopyridine agent that is indicated for the short term (< or = 4 weeks) treatment of insomnia (recommended dosage 10 mg/day in adults and 5 or 10 mg/day in the elderly or patients with hepatic impairment). Data have shown that the hypnotic efficacy of zolpidem is generally comparable to that of the benzodiazepines flunitrazepam, flurazepam, nitrazepam, temazepam and triazolam as well as nonbenzodiazepine hypnotic agents such as zopiclone and trazodone in the treatment of elderly and adult patients with insomnia. The comparative efficacy of a recently available nonbenzodiazepine hypnotic zaleplon and zolpidem has yet to be established. There was no evidence of tolerance developing to the hypnotic effects of zolpidem in a number of studies of up to 6 months' duration. However, tolerance has been described in a few patients taking the drug at high dosages for periods of up to several years. Zolpidem is well tolerated in patients with insomnia and the most common adverse events are generally nausea, dizziness and drowsiness. Although zolpidem produced some psychomotor and memory impairment over the first few hours after administration, it had few next-day effects (including effects on daytime well-being and morning coordination). In this respect, it was comparable or superior to flunitrazepam and flurazepam and comparable to other benzodiazepines in patients with insomnia. Zolpidem appears to have a low potential for abuse. Conclusions: Zolpidem is effective and well tolerated in patients with insomnia, including the elderly. Studies have shown that zolpidem generally has similar efficacy to other hypnotics including benzodiazepines and zopiclone. Zolpidem appears to have minimal next-day effects on cognition and psychomotor performance when administered at bedtime. In addition, there is little evidence of tolerance to the hypnotic effects of zolpidem, or rebound insomnia or withdrawal symptoms after discontinuation of the drug when it is given as recommended (10 mg/day for < 1 month) or over longer periods.     

Effects of zolpidem and flunitrazepam on nocturnal sleep of women subjectively complaining of insomnia

Eighteen non-pregnant woman complaining about insomnia were polysomnographically investigated for 3 nights with weekly intervals. They received placebo, 2 mg flunitrazepam or 10 mg zolpidem according to a cross-over double blind design. The patients were selected by general practitioners on the basis of subjective complaints. Zolpidem is a recently introduced short-acting imidazopyridine hypnotic, binding to a subunit of the benzodiazepine 1 receptor. Flunitrazepam is a well-known hypnotic, binding to both the benzodiazepine 1 and 2 receptor subtypes. Objective recording did not substantiate the subjective complaint of insomnia. Sleep patterns during placebo differed only little from that expected from age matched healthy persons. Both flunitrazepam and zolpidem significantly shortened sleep onset (5 min of continuous sleep beginning with NREM 1 sleep). The sleep composition following flunitrazepam was characterized by an increase in NREM 2, a prolongation of the time to REM sleep, a reduction of REM sleep and an increase in NREM 3–4 sleep during the first 2 h of sleep. The sleep composition following zolpidem resembled more that seen in persons without sleep complaints. However, as compared to placebo, there was a decrease of the time spent awake during sleep and an increase in NREM 3–4 during the first 2 of sleep.     

Pharmacology of an omega receptor agonist]

It has been suggested that different BZP (omega) receptor subtypes may mediate distinct behavioral effects of BZP receptor ligands. Several studies demonstrated that omega1 selective compounds are characterized by an increase in slow wave deep sleep with rapid onset of hypnotic action, and by reduced muscle relaxation, amnesic liability or tolerance. On the other hand, it is known that many different subtypes of GABAA receptors exist, based on the fact that many different subtypes can go into assembling GABAA receptors. GABAA receptors with alpha1 subunits may mediate sedative action and perhaps amnesia. Those with alpha2 subunits probably mediate anxiolytic actions. GABAA receptors with alpha3 subunits may regulate various neurotransmitters, and those with alpha5 subunits may also contribute to amnesia. Such discoveries could open up new avenues for drug development.     

Triazolam and zolpidem: effects on human memory and attentional processes

Rationale: The imidazopyridine hypnotic zolpidem may produce less memory and cognitive impairment than classic benzodiazepines, due to its relatively low binding affinity for the benzodiazepine receptor subtypes found in areas of the brain which are involved in learning and memory. Objectives: The study was designed to compare the acute effects of single oral doses of zolpidem (5, 10, 20 mg/70 kg) and the benzodiazepine hypnotic triazolam (0.125, 0.25, and 0.5 mg/70 kg) on specific memory and attentional processes. Methods: Drug effects on memory for target (i.e., focal) information and contextual information (i.e., peripheral details surrounding a target stimulus presentation) were evaluated using a source monitoring paradigm, and drug effects on selective attention mechanisms were evaluated using a negative priming paradigm, in 18 healthy volunteers in a double-blind, placebo-controlled, crossover design. Results: Triazolam and zolpidem produced strikingly similar dose-related effects on memory for target information. Both triazolam and zolpidem impaired subjects’ ability to remember whether a word stimulus had been presented to them on the computer screen or whether they had been asked to generate the stimulus based on an antonym cue (memory for the origin of a stimulus, which is one type of contextual information). The results suggested that triazolam, but not zolpidem, impaired memory for the screen location of picture stimuli (spatial contextual information). Although both triazolam and zolpidem increased overall reaction time in the negative priming task, only triazolam increased the magnitude of negative priming relative to placebo. Conclusions: The observed differences between triazolam and zolpidem have implications for the cognitive and pharmacological mechanisms underlying drug-induced deficits in specific memory and attentional processes, as well for the cognitive and brain mechanisms underlying these processes. Received: 8 June 1998/Final version: 15 December 1998     

Comparison of lindane, bicyclophosphate and picrotoxin binding to the putative chloride channel sites in rat brain and Torpedo electric organ.

The relative potencies of lindane, picrotoxin and several bicyclophosphate derivatives were compared in their ability to compete with 35S-t-butylbicyclophosphorothionate (35S-TBPS) binding sites in membranes derived from Torpedo electric organ and rat brain. Lindane proved to be ten times more potent in competing with 35S-TBPS binding in electric organ than rat brain, while the bicyclophosphate analogs displayed up to three orders of magnitude greater affinity for rat brain over electric organ. GABA inhibited 35S-TBPS binding in rat brain with moderate potency (IC50 = 30 microM), while unlabelled TBPS inhibited the binding of 3H-muscimol to the GABA receptor with an IC50 greater than 100 microM. The GABA receptor antagonist bicuculline increased 35S-TBPS binding in rat brain both in the presence and absence of 30 microM GABA. The results of the study are discussed in the context of a pharmacological discrimination between voltage-sensitive and receptor-gated Cl- channels in nervous tissue, with lindane and the i-propylbicyclophosphate derivative being the most selective compounds for discriminating between them.