Sigma-1 Receptor Antagonist Research Articles

Neurosteroids Ameliorate Conditioned Fear Stress: An Association with Sigma1 Receptors

Mice exhibited a marked suppression of motility (conditioned fear stress) when placed in an environment in which they had previously received an electric footshock. This conditioned fear stress response was dose-dependently attenuated by neurosteroids such as dehydroepiandrosterone sulfate (DHEAS; 25 and 50 mg/kg, s.c.) and pregnenolone sulfate (PREGS; 10–50 mg/kg, s.c.), and by a putative sigma1 receptor agonist, (+)-N-allylnormetazocine ((+)-SKF-10,047; 3 and 6 mg/kg, s.c.). However, progesterone (PROG; 10–50 mg/kg, s.c.) and allopregnanolone (5 and 20 mg/kg, s.c.) had no effect on this stress response. The attenuating effects of DHEAS (50 mg/kg, s.c.), PREGS (50 mg/kg, s.c.), and (+)-SKF-10,047 (6 mg/kg, s.c.) were reversed by NE-100 (5 mg/kg, i.p.), a sigma1 receptor antagonist and PROG (5 or 10 mg/kg, i.p.). When DHEAS (25 mg/kg) was co-administered with (+)-SKF-10,047 (3 mg/kg) at doses that do not affect the conditioned fear stress response by themselves, motor suppression was significantly attenuated. In mice showing the conditioned fear stress response, the serum concentration of DHEAS was lower than that in non-shocked mice. These results suggest that the attenuating effects of DHEAS and PREGS on the conditioned fear stress response are mediated via sigma1 receptors and that PROG has a sigma1 receptor antagonistic property. Further, the endogenous DHEAS may be involved in the expression of conditioned fear stress response in mice.

SH-SY5Y cells as a model for sigma receptor regulation of potassium-stimulated dopamine release

Previous studies in our laboratory using rat brain tissue have shown that neuropeptide Y (NPY) can enhance NMDA- and potassium-stimulated dopamine release from various brain regions and that this enhancement is reversed by sigma (σ) receptor antagonists. In the current study, we sought to determine whether SH-SY5Y cells are suitable for investigating σ receptor effects and whether any σ receptors present are of the subtype responsive to NPY. We compare mechanisms by which the prototypical σ receptor agonist (+)-pentazocine, and the proposed endogenous σ receptor ligand NPY regulate potassium-stimulated [ 3H]dopamine release from SH-SY5Y cells. Both (+)-pentazocine and NPY inhibit potassium-stimulated [ 3H]dopamine release. Unlike our studies in rat brain tissue, the effect of NPY on [ 3H]dopamine release is not reversed by σ receptor antagonists. SH-SY5Y cells appear to be an appropriate model to study the regulation of dopamine release by σ receptors or by NPY receptors, but this population is not identical to that population identified in brain slices.

Involvement of the sigma1 receptor in the cocaine-induced conditioned place preference.

The sigma1 (sigma1) receptor constitutes a particular target of cocaine believed to be involved in some of its behavioral effects. In the present study, its involvement in the rewarding effect of cocaine was examined using the conditioned place preference (CPP) procedure. CPP was induced in C57Bl/6 mice injected repeatedly with cocaine (20 mg/kg, i.p.). The selective sigma1 receptor antagonists NE-100 and BD1047 (1-10 mg/kg, i.p.) significantly attenuated or blocked the cocaine-induced CPP. Animals treated centrally with a sigma1 receptor antisense oligodeoxynucleotide failed to develop cocaine-induced CPP, unlike mismatch controls. The sigma1 receptor thus appears to be critically involved in the development of the cocaine-induced CPP and, in consequence, may constitute a promising approach to blocking cocaine reward.

(-)1-(Benzofuran-2-yl)-2-propylaminopentane shows survival effect on cortical neurons under serum-free condition through sigma receptors.

1. The rapid cell death of cortical neurons in serum-free culture was rescued by the condition medium from the high-density culture, but not by brain-derived neurotrophic factor or basic fibroblast growth factor. 2. Similar rescue was observed by the addition of (-)BPAP, an impulse enhancer, and (+)-pentazocine, a sigma receptor agonist. These actions were blocked by BD1063, a sigma receptor antagonist. 3. (-)BPAP showed a weak displacement activity in the [3H]pentazocine binding to synaptic membranes from rat cerebral cortex. 4. These findings suggest that (-)BPAP and (+)-pentazocine have unique survival activity on cortical neurons through sigma receptors.

3,4-dihydro-2(1H)-quinolinone as a novel antidepressant drug: synthesis and pharmacology of 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-3,4- dihydro-5-methoxy-2(1H)-quinolinone and its derivatives.

To develop a novel antidepressant drug with central nervous system-stimulating activity, we prepared a series of 1-[omega-(4-substituted phenyl-1-piperazinyl)alkyl]-3, 4-dihydro-2(1H)-quinolinone derivatives and examined their activities by their effects at 30 and 100 mg/kg po on the sleeping time of mice anesthetized with halothane and on the time required for recovery from coma induced in mice by cerebral concussion. We examined their binding affinities for sigma receptors by evaluating their ability to inhibit [(3)H]-1,3-di(o-tolyl)guanidine ([(3)H]DTG) binding to the rat whole brain membrane in comparison with three putative sigma receptor agonists: 1,3-di(o-tolyl)guanidine (DTG, 66), (+)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2, 6-methano-3-benzazecin-8-ol (SKF10,047, 67), and (+)-1,2,3,4,5, 6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2, 6-methano-3-benzazecin-8-ol (pentazocine, 68). Among the series of derivatives, 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-3, 4-dihydro-5-methoxy-2(1H)-quinolinone hydrochloride (34b) and its mesylate (34c), at a dose of 30 mg/kg po, reduced the sleeping time and the time for recovery from coma and they inhibited [(3)H]DTG binding for sigma receptors. The putative sigma receptor agonists reduced the sleeping time and the time for recovery from coma whereas two sigma receptor antagonists, alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol hydrochloride (BMY14802, 69) and cis-9-[3-(3, 5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride (rimcazole, 70), were inactive in the two tests. Preadministration of the putative sigma receptor antagonists 69 (3 mg/kg po) and 70 (30 mg/kg po) completely antagonized the actions of 34b and the sigma receptor agonists in the test for recovery from coma. These results suggested that 34b and 34c are sigma receptor agonists. Furthermore, a single administration of 1 and 10 mg/kg po 34b and 34c showed antidepressant-like activity by reducing the immobility time in the forced-swimming test with mice, while a tricyclic antidepressant, 10, 11-dihydro-N,N-dimethyl-5H-dibenz[b,f]azepine-5-propanamine hydrochloride (imipramine, 1) (10 and 30 mg/kg po), did not reduce the time after a single administration. 1 reduced the time after repeated administration of 30 mg/kg po once a day for 4 days. The structure-activity relationship of the series of compounds is also discussed.

The attenuation of learning impairments induced after exposure to CO or trimethyltin in mice by sigma (sigma) receptor ligands involves both sigma1 and sigma2 sites.

1. Sigma (sigma) receptor ligands were previously reported to alleviate learning and memory impairments on several pharmacological and pathological rodent models of amnesia. Such effect was demonstrated as involving the sigma1 subtype of sigma receptor. 2. In this study, we characterized the pharmacological effect mediated by sigma ligands on two lesional models of amnesia in mice: (1) the hypoxia-related learning and memory impairment model induced by repeated exposure to carbon monoxide (CO) gas; and (2) the intoxication with trimethyltin (1 mg kg(-1)). 3. The selective sigma1 ligand PRE-084 (1 mg kg(-1)) or the non-selective sigma1/sigma2 compounds DTG (0.1 mg kg(-1)), BD1008 (3 mg kg(-1)), and haloperidol (0.1 mg kg(-1)) reversed significantly the spontaneous alternation deficits observed 7 days after exposure to CO or 14 days after intoxication with trimethyltin. 4. The selective sigma1 receptor antagonist NE-100 (1 mg kg(-1)) was ineffective by itself, but blocked completely the PRE-084 effects, partially the DTG effects, and did not affect the effects induced by BD1008 or haloperidol. 5. A similar pharmacological profile was observed in the step-down type passive avoidance test performed 8 days after exposure to CO. 6. These results show that, in contrast to the previously reported amnesia models, the impairments induced after exposure to CO or intoxication with trimethyltin could be alleviated not only by sigma1 receptor agonists but also by sigma2 agonists. The particular pattern of neurodegeneration observed in these lesional models may explain these differences.

Design, synthesis, structure-activity relationships, and biological characterization of novel arylalkoxyphenylalkylamine sigma ligands as potential antipsychotic drugs.

sigma Receptor antagonists may be effective antipsychotic drugs that do not induce motor side effects caused by ingestion of classical drugs such as haloperidol. We obtained evidence that 1-(2-dipropylaminoethyl)-4-methoxy-6H-dibenzo[b,d]pyran hydrochloride 2a had selective affinity for sigma receptor over dopamine D2 receptor. This compound was designed to eliminate two bonds of apomorphine 1 to produce structural flexibility for the nitrogen atom and to bridge two benzene rings with a -CH2O- bond to maintain the planar structure. In light of the evidence, N, N-dipropyl-2-(4-methoxy-3-benzyloxylphenyl)ethylamine hydrochloride 10b was designed. Since compound 10b had eliminated a biphenyl bond of 6H-dibenzo[b,d]pyran derivative 2a, it might be more released from the rigid structure of apomorphine 1 than compound 2a. The chemical modification of compound 10b led to the discovery that N, N-dipropyl-2- [4-methoxy-3-(2-phenylethoxyl)phenyl]ethylamine hydrochloride 10g (NE- 100), the best compound among arylalkoxyphenylalkylamine derivatives 3, had a high and selective affinity for sigma receptor and had a potent activity in an animal model when the drug was given orally. We report here the design, synthesis, structure-activity relationships, and biological characterization of novel arylalkoxyphenylalkylamine derivatives 3.

Sigma-receptor ligands and anti-stress actions

The functional role of sigma receptors in the central nervous system has been investigated extensively. Sigma1-receptors have been shown to play an important role in antidepressive effects since selective sigma1-receptor agonists, as well as typical antidepressants, reduced the immobility time in the forced swimming and tail suspension tests. The reduction of immobility by sigma1-receptor agonists is antagonized by NE-100, a sigma1-receptor antagonist. It has been suggested that sigma receptors are involved in anxiety since Lu 28-179, a sigma2-receptor agonist, has anxiolytic properties in rodents. In addition to the depressive animal model, phenytoin-sensitive sigma1-receptor agonists such as (+)-SKF-10,047 and dextromethorphan attenuate the conditioned fear stress (CFS) response (which is not influenced by typical anxiolytics and antidepressants) in rodents, the attenuating effects being mediated through phenytoin-sensitive sigma1 receptors, which are closely connected to the mesolimbic dopaminergic systems. Furthermore, neurosteroids such as dehydroepiandrosterone sulfate also attenuate the CFS response, the effect being mediated via sigma1 receptors. These findings suggest that sigma receptors are involved in stress-induced pathophysiological changes such as depression and anxiety and that phenytoin-sensitive sigma1-receptor ligands are useful for the treatment of affective disorders, particularly those considered to be treatment-resistant.

Atypical antipsychotic profiles of sigma receptor ligands

This is a review on the recent results of research on sigma-receptor antagonists. NE-100, a selective sigma1-receptor antagonist, shows improvement of abnormal behaviors and cognitive dysfunction induced by phencyclidine (PCP). However, NE-100 does not inhibit dopamine agonist-induced behaviors nor induces catalepsy. The mode of action of NE-100 is estimated to be the indirect modulation of the NMDA/PCP-receptor ion channel complex and the modulation of dopamine release from the dopaminergic nerve terminals. The recently reported MS-355/MS-377, which is also a selective sigma1-receptor antagonist, has a similar pharmacological profiles as NE-100, but in addition, MS-355/MS-377 inhibits methamphetamine-induced formation of reversal tolerance and also inhibits apomorphine-induced climbing behavior like dopamine D2-receptor antagonists. The report on clinical trial targeting schizophrenia shows results on rimcazole, remoxipride, BMY 14802, panamesine (EMD 57445) and SL 82.0715. Rimcazole was effective in the open study, but the double blind trial was discontinued due to seizure induction. Remoxipride showed efficacy different from those of dopamine D2-receptor antagonists (less extrapyramidal adverse effects), but the trial was discontinued due to occurrence of aplastic anemia. Panamesine and SL 82.0714 showed favorable efficacy in the open studies, but BMY 14802 showed no efficacy in clinical trials.

Rimcazole, a sigma receptor ligand, and the anticonvulsive action of conventional antiepileptic drugs.

Rimcazole (a selective sigma receptor antagonist) at 5 and 10 mg/kg, 30 min before the test, lowered the electroconvulsive threshold, being ineffective at 2.5 mg/kg. Rimcazole (2.5 and 5 mg/kg) enhanced the protective activity of phenobarbital and valproate, but not that of carbamazepine and diphenylhydantoin against maximal electroshock. The effect of rimcazole upon the electroconvulsive threshold was reversed by haloperidol (0.5 mg/kg), but the rimcazole-induced potentiation of the anticonvulsive action of antiepileptics was not. Moreover, rimcazole (2.5 mg/kg) did not alter the total or free plasma levels of valproate or phenobarbital, so a pharmacokinetic interaction is not probable. The combined treatment of rimcazole with antiepileptic drugs, providing a 50% protection against maximal electroshock, did not affect motor performance in mice, although it resulted in significant long-term memory deficits. Our data indicate that rimcazole, in spite of lowering the seizure threshold, may enhance the protective activity of some antiepileptic drugs.

Microinjection of sigma ligands into cranial nerve nuclei produces vacuous chewing in rats

Many typical neuroleptics carry a high risk for producing motor side effects in humans, and have significant affinities for sigma (sigma) receptors. Sigma receptors are densely concentrated in cranial nerve nuclei that comprise the final common pathways for lingual, facial and masticatory movements; thus, they may serve as important substrates for some of the unwanted movements that can accompany neuroleptic treatment. Therefore, the purpose of this study was to evaluate whether microinjection of sigma ligands into the facial nucleus or spinal trigeminal nucleus, oralis would cause orofacial dyskinesias, and whether these effects could be attenuated with sigma receptor antagonists. Microinjection of the high affinity sigma ligands, di-o-tolylguanidine or haloperidol (0-10 nmol/0.5 microl), produced a marked increase in vacuous chewing and facial tremors in rats, while coadministration of the functional sigma antagonists, BD1047 or BD1063 (5 nmol), greatly attenuated these drug-induced movements. Sulpiride and clozapine (10 nmol/0.5 microl), sigma inactive/dopamine active atypical antipsychotic drugs with a much reduced risk for producing motor side effects in humans, were unable to elicit orofacial dyskinesias when microinjected into the facial or spinal trigeminal nucleus, oralis. These studies indicate that sigma receptors may contribute to some forms of motor side effects resulting from antipsychotic drug treatment.

Electrophysiological Study, Biodistribution in Mice, and Preliminary PET Evaluation in a Rhesus Monkey of 1-Amino-3-[ 18F]fluoromethyl-5-methyl-adamantane ( 18F-MEM): A Potential Radioligand for Mapping the NMDA-Receptor Complex

The effect of the fluorinated memantine derivative and NMDA receptor antagonist, 1-amino-3-fluoromethyl-5-methyl-adamantane ( 19F-MEM), at the NMDA receptor ion channel was studied by patch clamp recording. The results showed that 19F-MEM is a moderate NMDA receptor channel blocker. A procedure for the routine preparation of the 18F-labelled analog 18F-MEM has been developed using a two-step reaction sequence. This involves the no-carrier-added nucleophilic radiofluorination of 1-[ N-(tert-butyloxy)carbamoyl]-3-(toluenesulfonyloxy)methyl-5-methyl-adamantane and the subsequent cleavage of the BOC-protecting group using aqueous HCl. The 18F-MEM was obtained in 22 ± 7% radiochemical yield (decay-corrected to EOB) in a total synthesis time including HPLC purification of 90 min. A biodistribution study after IV injection of 18F-MEM in mice showed a fast clearance of radioactivity from blood and relatively high initial uptake in the kidney and in the lung, which gradually decreased with time. The brain uptake was high (up to 3.6% ID/g, 60 min postinjection) with increasing brain-blood ratios: 2.40, 5.10, 6.33, and 9.27 at 5, 30, 60, and 120 min, respectively. The regional accumulation of the radioactivity in the mouse brain was consistent with the known distribution of the PCP recognition site. Preliminary PET evaluation of the radiotracer in a rhesus monkey demonstrated good uptake and prolonged retention in the brain, with a plateau from 35 min onwards p.i. in the NMDA receptor-rich regions (frontal cortex, striata, and temporal cortex). Delineation of the hippocampus, a region known to contain a high density of NMDA receptors, was not possible owing to the resolution of the PET tomograph. The regional brain uptake of 18F-MEM was changed by memantine and by a pharmacological dose of (+)-MK-801, indicating competition for the same binding sites. In a preliminary experiment, haloperidol, a dopamine D2 and sigma receptor antagonist, decreased the binding of 18F-MEM from the brain regions examined, suggesting that binding was also occurring to the sigma recognition sites.

Hypersusceptibility to DMCM-induced seizures during diazepam withdrawal in mice: evidence for upregulation of NMDA receptors.

The present study investigated the role of NMDA (N-methyl-D-aspartate) receptors in the hypersusceptibility to seizures induced by the benzodiazepine inverse agonist DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) during diazepam withdrawal in mice, using behavioral and biochemical approaches. The seizure threshold of DMCM was markedly decreased during diazepam withdrawal, reflecting withdrawal hyperexcitability in response to physical dependence. The decrease in the seizure threshold of DMCM in diazepam-withdrawn mice was inhibited by the non-competitive NMDA receptor antagonists MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate; 50 microg/kg, s.c.) and ifenprodil (20 mg/kg, i.p.). The effective doses of these compounds were lower than those required to prevent DMCM-induced seizures in chronically vehicle-treated mice. Since MK-801 and ifenprodil do not only bind to NMDA receptors but also to sigma receptors, the present study also investigated the effects of sigma receptor ligands. The decrease in the seizure threshold of DMCM in diazepam-withdrawn mice was not modified by the sigma receptor agonist, (+)-pentazocine (5 mg/kg, s.c.), or the sigma receptor antagonist, NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride; 5 mg/kg, i.p.). Furthermore, the latency to the expression of wild running induced by intracerebroventricular administration of NMDA (60 ng/mouse) was also significantly lower in diazepam-withdrawn mice than in vehicle-treated control mice. On the other hand, there was no difference in the spermidine concentration between vehicle-treated control and diazepam-withdrawn mice. In a receptor binding experiment, the Bmax value for [3H]-MK-801 binding was significantly increased in cerebrocortical tissues from diazepam-withdrawn mice, while the Kd value did not change in either group. However, the acute addition of a high concentration of diazepam (10 and 100 microM) in vitro did not alter [3H]-MK-801 binding in cerebrocortical membrane preparations. The behavioral experiments suggest that NMDA receptor antagonists may suppress benzodiazepine withdrawal responses, while the biochemical study reveals upregulation of the NMDA receptor, which may play an important role in the hypersusceptibility to DMCM-induced seizure in diazepam-withdrawn mice.

Release of [3H]dopamine from guinea pig striatal slices is modulated by sigma1 receptor agonists.

Sigma receptors are found in motor and limbic areas in the brains of humans, non-human primates, and rodents. The most extensive pharmacological studies of ligand binding to sigma receptors have utilized brain tissue from guinea pigs, where two subtypes of sigma receptor, designated sigma1 and sigma2, have been identified. Few functional roles for sigma receptors have been described. Their location in guinea pig striatum, a terminal field of dopaminergic projections arising from the substantia nigra, suggested that this tissue would be a logical choice in which to examine physiological properties of sigma receptor activation. We found that sigma1 receptor agonists inhibited N-methyl-D-aspartate-stimulated [3H]dopamine release from guinea pig striatal slices in a concentration-dependent manner. The inhibition by sigma1 receptor agonists was reversed by a selective sigma1 receptor antagonist, as well as by a non-subtype-selective sigma receptor antagonist. The ability of agonists working through sigma1 receptors, but not through sigma2 receptors, to inhibit the stimulated release of catecholamines appears to be a unique characteristic of guinea pig striatum. We have previously reported that in rat striatum and hippocampus, as well as in guinea pig nucleus accumbens, prefrontal cortex, and hippocampus, activation of either sigma receptor subtype inhibits such release. Stimulated release of [3H]dopamine from guinea pig striatum was also inhibited by the phencyclidine receptor agonist dizocilpine, but this inhibition was not reversed by the sigma receptor antagonists. Therefore, the inhibition produced by sigma receptor agonists was not mediated via the phencyclidine binding site within the N-methyl-D-aspartate-operated cation channel. Our findings support the hypothesis that sigma receptor activation provides a mechanism of modulating dopamine release from striatum, and that striatal tissue from guinea pigs appears to be an appropriate model for characterizing sigma1 receptor-mediated effects.

Solubilization and characterization of binding sites for [3H]NE-100, a novel and potent sigma 1 ligand, from guinea pig brain.

The binding sites for [3H]NE-100, a newly defined sigma 1 ligand, was solubilized from guinea pig brain, using zwitterionic detergent 3-[(3-c holamidopropyl) dimethylamino]-1-propanesulfonate (CHAPS), and the properties of the solubilized binding sites were compared to those for [3H](+)-pentazocine, a selective sigma 1 ligand. The pharmacological selectivity of solubilized sites for both [3H]NE-100 and [3H](+)-pentazocine was identical to that obtained from membrane preparations. Stereoselectivity of benzomorphan such as pentazocine and SKF10,047 was preserved in displacing [3H]NE-100 binding in solubilized preparations as observed in membrane preparations. The inhibitory potencies of several sigma ligands on [3H]NE-100 binding were similar to those on [3H](+)-pentazocine binding, indicating that the pharmacological characteristics of the binding sites for [3H]NE-100 are retained after solubilization. Phenytoin augmented the binding of [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl) piperidine hydrochloride (3-PPP) to solubilized sigma binding sites while it had no effect on the binding of [3H]NE-100. Furthermore, the inhibitory effect of putative sigma receptor agonists such as (+)-3-PPP and dextromethorphan were enhanced by phenytoin; the effects of haloperidol, a putative sigma receptor antagonist, were unaltered. Molecular weight of [3H]NE-100 binding protein was estimated to be 440KDa by Sepharose CL-6B gel filtration chromatography, and the value was identical to that of [3H](+)-pentazocine binding protein, a putative sigma 1 binding protein. These findings indicate that [3H]NE-100 binding sites are putative sigma 1 binding sites, and that NE-100 may act as an antagonist at sigma 1 binding sites.

σ Receptor Modulation of Noradrenergic‐Stimulated Pineal Melatonin Biosynthesis in Rats

Because sigma receptors are richly concentrated in the rat pineal gland, the present study was performed to investigate their possible role in the modulation of melatonin production. To this purpose, we assessed in vivo the effects of the sigma-receptor ligands 1,3-di(2-tolyl)guanidine and (+)-N-allylnormetazocine on the rat pineal gland activity during either the daytime or the nighttime. Compared with vehicle, 1,3-di(2-tolyl)guanidine and (+)-N-allylnormetazocine potentiated the enhancement of N-acetyltransferase activity and pineal melatonin content induced by isoproterenol administration during the daytime, whereas they did not affect the diurnal basal biosynthetic activity of the gland. Conversely, at night, 1,3-di(2-tolyl)guanidine and (+)-N-allylnormetazocine enhanced significantly the physiological increases in both pineal N-acetyltransferase activity and melatonin levels. This enhancement was prevented by pretreatment with rimcazole, a specific sigma-receptor antagonist. These findings suggest that, in rats, the activation of pineal sigma-receptor sites does not affect the biosynthetic activity of the pineal gland during daytime, whereas it potentiates the production of melatonin when the gland is noradrenergically stimulated either by isoproterenol administration or by the endogenously released norepinephrine at nighttime.

NE‐100: A Novel Sigma Receptor Antagonist

NE‐100: A Novel Sigma Receptor Antagonist

1,3-di- o-Tolylguanidine (DTG) differentially affects acute and tonic formalin pain: Antagonism by rimcazole

The role of the sigma receptor in prolonged pain was examined by assessing the effects of 1,3, di- o-tolylguanidine (DTG), a selective sigma receptor ligand, on the formalin test in mice. Formalin injected subcutaneously into the hindpaw produces a biphasic pain response: an acute phase of short duration followed by a longer-lasting tonic phase. DTG (10 mg/kg, IP) potently reduced pain behavior in the acute phase but increased pain behavior in the tonic phase. Rimcazole (5 and 10 mg/kg, IP), a selective sigma receptor antagonist, blocked both the DTG-induced decrease and increase in pain behavior observed in the acute and tonic phases, respectively. These data support previous findings indicating a modulatory role for the sigma receptor in nociceptive processes, and suggest that this receptor differentially modulates acute vs. tonic pain.

The effects of sigma ligands on protein release from lacrimal acinar cells: a potential agonist/antagonist assay

Sigma (σ) receptor antagonists have been proposed as leading clinical candidates for use in various psychotic disorders. Prior to clinical testing, it is imperative that a new agent be correctly identified as an antagonist and not an agonist since the latter may worsen the psychosis. For σ-ligands many behavioral and pharmacological assays have been developed in an attempt to classify agonist/antagonist activity. These assays evaluate a response or a behavior in an animal model that can be related to clinical efficacy. However, is the action by the presumed antagonist a consequence of σ-receptor activity? Previously we have identified σ-receptors in acinar cells of the main lacrimal gland of the New Zealand white rabbit and have measured protein release after the addition of various N,N-disubstituted phenylalkylamine derivatives known to be σ-ligands by receptor binding studies. Although protein release from acinar cells has been attributed to either muscarinic or a-adrenergic stimulation, protein release from σ-receptor stimulation was also confirmed. In the reported studies here, we isolated and incubated acinar cells with varying concentrations of known σ-ligands and measured protein concentration. A knowledge of the receptor profile for the disubstituted phenylalkylamines permitted experiments to be designed in which various α, muscarinic, serotonergic and dopaminergic antagonists could be added in equimolar concentrations. Under the conditions of these experiments, statistically significant increases in protein release for σ-ligands could be attributed to stimulation of a-receptors. Haloperidol, an apparent σ-antagonist, caused a statistically significant decrease in protein release and also inhibited protein release when tested with a known σ-ligand, AF2975 [N,N-dimethyl-2-phenylethylamine]. In this system, stimulation and inhibition of protein release were defined as agonist and antagonist behavior, respectively. Of particular interest were the results for BMY 14802 and +/- pentazocine, both of which were found to be agonists. Various antipsychotic and antidepressant drugs were measured for their agonist/antagonist behavior. Because of multireceptors present in acini, their agonist or antagonist behavior could not be attributed solely to interaction with the σ-receptor unless specific antagonists were added.

A role of sigma receptors on hypoxia/hypoglycemia-induced decrease in CA1 presynaptic fiber spikes in rat hippocampal slices

Effects of sigma receptor agonists or antagonists on hypoxia/hypoglycemia-induced decrease in CA1 presynaptic fiber spikes elicited by the stimulation of Schaffer collaterals were investigated using rat hippocampal slices. Treatment with sigma receptor antagonists such as haloperidol. NE-100 and rimcazole produced a concentration-dependent attenuation of the hypoxia/hypoglycemia-induced decrease in CA1 presynaptic fiber spikes. The order of potency of protection against hypoxia/hypoglycemia-induced reduction in CA1 presynaptic potential was: NE-100 = haloperidol > rimcazole. Treatment with sigma receptor agonist DTG potentiated the hypoxia/hypoglycemia-induced decrease in the CA1 presynaptic potential, whereas SKF10047 which possesses an affinity for phenycyclidine site attenuated the decrease of potential. NE-100 antagonized a functional deficit induced by DTG, but unaffected the improving effect induced by SKF10047. The present results suggest a facilitatory role of sigma receptor stimulation in hypoxia/hypoglycemia-induced an impairment of neurophysiological functions in CA1 presynaptic regions of hippocampal slices.