Cns drugs 2004; 18 (5): 269-284

CNS Drugs 2004; 18 (5): 269-284  2004 Adis Data Information BV. All rights reserved.
σ-1 Receptor Ligands
Potential in the Treatment of Neuropsychiatric Disorders
Teruo Hayashi and Tsung-Ping Su Cellular Pathobiology Unit, Cellular Neurobiology Research Branch, Intramural ResearchProgram, Department of Health and Human Sciences, National Institute on Drug Abuse,National Institutes of Health, Baltimore, Maryland, USA The σ receptor was originally proposed to be a subtype of the opioid receptor.
However, it is now clear that σ receptors are unique non-opioid,non-phencyclidine brain proteins. Two types of σ receptor exist, the σ-1 receptorand the σ-2 receptor. σ-1 receptors have been cloned and their distribution,physiological functions and roles in signal transduction were recently character-ised. Certain sex hormones in the brain (neurosteroids) are known to interact with σ-1 receptors. σ-1 receptors regulate glutamate NMDA receptor function and therelease of neurotransmitters such as dopamine. They are thus proposed to beinvolved in learning and memory as well as in certain neuropsychiatric disorders.
Selective σ-1 receptor ligands have been suggested to represent a new class of therapeutic agents for neuropsychiatric disorders, although none have yet beenintroduced into therapeutic use. Early studies showed that psychotomimeticbenzomorphans, as well as several antipsychotics, can bind to σ-1 receptors. As aresult of these findings, σ-1 receptor ligands have been proposed as being ofpotential use in the treatment of schizophrenia. Nevertheless, the relationship of σ-1 receptors to the underlying pathogenesis of schizophrenia is still unclear. σ-1receptor ligands have failed to improve acute psychotic symptoms of schizo-phrenia in clinical trials, but, interestingly, a few studies have shown an improve-ment in negative symptoms in schizophrenic patients.
A number of preclinical studies have shown that selective agonists of σ-1 receptors affect higher-ordered brain functions such as learning and memory,cognition and mood. These studies indicate that σ-1 receptor agonists may exerttherapeutic effects in depression and senile dementia. Indeed, the σ-1 receptoragonist igmesine, has been shown to improve depression in a clinical trial. Themost distinctive feature of the action of σ-1 receptor ligands is their ‘modulatory'role. In behavioural studies of depression and memory, they exert beneficialeffects only when brain functions are perturbed.
Given the recently accumulated preclinical and clinical data, it is time to reconstruct the concept of σ-1 receptors and the associated pathophysiologicalconditions that ligands of these receptors target. This would allow clinical trials tobe performed more efficiently, and the results may confirm a long-speculatedpossibility that σ-1 receptor ligands represent a new class of therapeutic agents forneuropsychiatric disorders.
σ receptors were originally proposed by Martin benzomorphans such as SKF-10047 (N-allyl- et al.[1] to be a subtype of opioid receptor. Since normetazocine) and pentazocine are known to bind Hayashi & Su selectively to σ receptors and cause delusions and introduction into clinical trials. However, recently hallucinations in animals and humans,[1-6] Martin et accumulated evidence on σ-1 receptors from basic al.[1] speculated that these drugs have a and preclinical research has resulted in a significant psychotomimetic action through an interaction with advance in our understanding of this orphan recep- σ receptors. However, a series of later experiments tor. In particular, behavioural studies using animals demonstrated that the σ receptor is insensitive to have contributed greatly to understanding the physi- naloxone, a universal antagonist of opioid recep- ological function of σ-1 receptors.
tors,[7,8] and confirmed that the σ receptor is a non- In this article, findings on σ-1 receptors from opioid receptor. However, because SKF-10047 can preclinical and clinical research are summarised, bind to the phencyclidine (PCP) site on glutamate and the physiological function of σ-1 receptors, as NMDA receptors and, conversely, PCP can bind to well as the potential therapeutic targets of σ-1 recep- the σ receptor, confusion arose between the σ recep- tor ligands in clinical pharmacotherapy, discussed.
tor and the PCP site on NMDA receptors.[9] Furtherexperiments using more selective ligands for the σ 1. σ-1 Receptors
receptor, such as (+)-3-(3-hydroxyphenyl)-N-propylpiperidine [(+)-3-PPP] and for the PCP site, such as thienylcyclohexylpiperidine (TCP), showedthat the binding sites and brain distribution of σ and The σ-1 receptor was originally identified using a NMDA receptors are different,[10-13] leading to the dextrorotatory isomer of the benzomorphan conclusion that the σ receptor is a non-opioid, non- SKF-10047 [(+)SKF-10047],[7,9-11,13] and further PCP unique brain-enriched receptor.
characterised by more selective compounds such as Data from receptor binding studies indicate that (+)pentazocine.[19] (–)-Isomers [e.g. (–)SKF-10047] at least two subtypes of σ receptor exist: σ-1 (high have significantly lower affinities for the σ-1 recep- affinity site) and σ-2 (low affinity site) receptors.[14] The σ-1 receptor was cloned in 1996.[15] The cloned It is now known that many structurally diverse protein contains an endoplasmic reticulum (ER) re- compounds can bind to the σ-1 receptor (table I).
tention signal (therefore residing at the ER) and at Interestingly, several clinically used psychotropic least one putative transmembrane domain.[15-18] The drugs such as haloperidol, imipramine and SSRIs σ-2 receptor has not been cloned.
can bind to the receptor with low nanomolar affini- In this article, we focus on the σ-1 receptor. As ty.[7,20-23] Some σ-1 receptor ligands such as halo- mentioned above, some benzomorphans that can peridol, NE-100 and MS-377 have been shown to bind to the σ-1 receptor are known to cause psycho- block, especially in in vivo studies, the action of sis in humans.[2,4-6] Furthermore, it was discovered (+)pentazocine and other selective σ-1 ligands and, in the 1980s that some antipsychotics, especially therefore, have been categorised as σ-1 receptor haloperidol, have relatively high affinities for σ-1 antagonists.[24,25] However, it is still unclear exactly receptors.[7] Thus, σ-1 ligands were originally pro- which pharmacological actions exerted by these posed to be a new class of antipsychotics for the therapeutic compounds are mediated by the σ-1 treatment for schizophrenia. However, until the ear- receptor.[7,20,22,23] As such, in drug development, in ly 1990s, methods for studying the σ-1 receptor addition to receptor binding assays, a thorough eval- were confined to mainly receptor binding assays and uation of σ-1 ligands by recently established in vitro there were no established biochemical and behav- and in vivo assays (see sections 1.3 and 2.1) is ioural tools to characterise the agonist-antagonist necessary, as evidence from binding assays alone action of σ-1 ligands and their implications for may not be sufficient to fully characterise the ligand.
certain neurophysiological conditions. In addition, In other words, more criteria should be applied when endogenous ligands, intracellular signal transduc- interpreting a pharmacological action of ‘so-called' tion and receptor localisation had not been clarified.
σ receptor ligands, as the compounds that have These impeded the identification of the specific affinity for the σ binding site may not always be therapeutic targets of σ-1 receptor ligands and their selective and functional.
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CNS Drugs 2004; 18 (5) σ-1 Receptors in Neuropsychiatric Disorders Table I. σ-1 receptor ligands
Subtype selectivity Function Also binds to the PCP site Highly selective agonist Dopamine receptor agonist Dopamine D2 receptor antagonist Monoamine reuptake inhibitor Partial agonist in some assays Pregnenolone sulphate PB-008 (dihydroepiandrosterone sulphate) Dopamine transporter inhibitor Other synthetic compounds
Igmesine (JO-1784) High affinities for both σ-1receptor and C8-C7 sterolisomerase Serotonin 5-HT1A receptoragonist Rimcazole (BW-234U) Ineffective against the positivesymptoms of schizophrenia[27]b BMS-181100 (BMY-14802) Ineffective against the positivesymptoms of schizophrenia[28]c Panamesin (EMD-57445) Effective against the positive/negative symptoms ofschizophrenia[29,30]d Metabolite is a dopamineantagonist Eliprodil (SL-82.0715) Effective against negativesymptoms of schizophrenia[31]d Glutamate NMDA polyamine siteantagonist Inhibition constant (Ki) values, where +++ indicates <50 nmol/L, ++ indicates <500 nmo/L and + indicates <10 µmol/L.
Double-blind study.
Single-blind study.
Open-label study.
3-PPP = 3-(3-hydroxyphenyl)-N-propylpiperidine; DTG = 1,3-di-o-tolylguanidine; PCP = phencyclidine.
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CNS Drugs 2004; 18 (5)

Hayashi & Su Sex steroid hormones such as progesterone and tritiated benzomorphans may contain multiple sites pregnenolone sulphate are known to bind to the σ-1 including the σ-1 receptor.[50-52] receptor.[32] These hormones are synthesised denovo in the brain (and are termed neurosteroids) and 1.3 Effect on Cellular Function are known to regulate NMDA and GABAA recep-tor-coupled channels.[33] Specifically, progesterone As mentioned in section 1.2, recent studies using possesses a significant affinity for the σ-1 receptor a specific antibody against the σ-1 receptor suggest at physiologically relevant concentrations; the affin- that the receptor exists predominantly on the ER, ity of progesterone at the σ-1 receptor has been especially the smooth ER.[47,53] In the rat primary shown to be about 250 nmol/L in binding stud- neuron, we found that the majority of σ-1 receptors ies.[32,34] Brain levels of neurosteroids are known tobe affected by aging, emotion and certain patho-physiological states such as dementia and depres-sion.[33,35-37] Several behavioural and physiological experiments suggest the involvement of σ-1 recep- Lung HeartAortaVein tors in certain behaviours caused by neuroster- oids.[38-41] The physiological relevance of neuroster- oid binding to σ-1 receptors has been under intense Pancreas renal glandpose tissue -1 receptors are present in high density in the CNS. The early experiments using binding assaysand autoradiography suggested that σ-1 receptorsare enriched in several brain regions including thecerebellum, and exist also at a high density in theliver and adrenal gland.[10-12,42-44] σ-1 receptors are enriched in microsomal mem- branes from the brain,[45] suggesting that they maylocalise on the endoplasmic reticulum (ER).
After the cloning of the σ-1 receptor, it became possible to measure the mRNA and protein levels of σ-1 receptors using nucleotide probes or anti-bodies.[46,47] mRNA of σ-1 receptors is expressed atmoderate levels in the brain and several peripheralorgans including the stomach, liver, adrenal glandand testis.[15-17] However, protein levels measuredby a specific antibody against σ-1 receptors exhibitquite a different pattern (figure 1),[48,49] with thelevel being highest in the brain, spinal cord andperipheral nerves, but is lower in peripheral organs Fig. 1. Cellular and whole body distribution of σ-1 receptors. (a)
including the liver and adrenal grand. Furthermore, Body distribution of σ-1 receptors in the mouse. Protein extractsfrom each organ or region were separated by sodium dodecyl in the brain, the σ-1 receptor protein level is high in sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and blot- the frontal cortex, hippocampus, and striatum, but ted by a σ-1 receptor antibody. (b) A rat brain primary neuron
lower in the cerebellum.[48,49] Therefore, the distri- expressing yellow fluorescent protein (YFP)-tagged σ-1 receptors(shown in white). EYFP-N vectors (clontech) containing σ-1 re- bution of the σ-1 receptor protein is much more ceptor cDNA were transfected to neurons from the postnatal rat restricted than previously reported. The distribution brain. The cell body is indicated by the arrow and the dendrites by of σ-1 binding sites as originally characterised by the arrowheads. N = nucleus.
 2004 Adis Data Information BV. All rights reserved.
CNS Drugs 2004; 18 (5) σ-1 Receptors in Neuropsychiatric Disorders are localised on the ER of the cell body and the search is needed to understand the mechanisms by dendrites, and are highly clustered (figure 1).[48] which the σ-1 receptor modulates diverse types of These results are consistent with the enrichment of ion channels on the plasma membrane.
σ-1 binding sites in brain microsomes[45] and with As mentioned in section 1.1, tricyclic antidepres- the existence of an ER retention motif on the N- sants and SSRIs possess high affinity for the σ-1 terminus of the cloned σ-1 receptor.[15] receptor.[7,20,22,23] We recently found that these anti- Recent studies using green fluorescence protein- depressants potentiate nerve growth factor-induced fused σ-1 receptors demonstrated that the receptors neurite growth in PC-12 cells via σ-1 receptors.[64] localise on lipid droplets associated with the ER in Therefore, the affinity of these antidepressants for addition to being on the ER reticular network.[1,54,55] the σ-1 receptor may contribute to certain pharma- Functional dominant negative σ-1 receptors failed to cological actions, specifically their neurotropic ac- target ER-lipid droplets, which led to retention of neutral lipids and cholesterol in the ER, a decrease Several lines of research demonstrated that the of cholesterol in plasma membranes and a bulbous σ-1 receptor modulates neuronal firing and neuro- aggregation of ER.[54] The ER synthesises most transmitter release.[41,65-67,93-96] Monnet et al.[66] lipids inside cells and exports them to the periphery found that σ-1 receptor ligands, although exhibiting of cells for the constitution of the plasma membrane.
no effect by themselves, selectively enhance Therefore, these findings suggest that σ-1 receptors NMDA-induced neuronal firing in the CA3 region on the ER regulate the compartmentalisation and of hippocampus in rats. σ-1 receptor ligands also export of ER lipids, and the resultant are lipid com- modulate NMDA-mediated neuronal firing in the positions in the plasma membranes. Interestingly, CA1 region in a biphasic dose-response manner.[65] upon stimulation with σ-1 receptor agonists, σ-1 A 2-day treatment with σ-1 receptor agonists mark- receptors can translocate at the ER (i.e. from ER edly increases neuronal firing of serotonergic neu- lipid droplets to periphery ER networks that are rons in the dorsal raphe nucleus.[67] Interestingly, a close to the plasma membrane or to the tips of selective σ-1 receptor agonist SA-4503 potentiates neurites[55]). The physiological role of σ-1 receptor dopamine neuronal activity in ventral regimental translocation is unknown at present; however, be- area, but supresses it in substantia nigra pars com- cause σ-1 receptors specifically target ER lipid pacta in the rat brain.[68] On the other hand, σ-1 droplets and compartmentalise neutral lipids, the receptor ligands were shown to modulate depo- dynamic translocation of the receptors might affect larisation-induced dopamine release from brain lipid transport and distribution in neuronal cells.
slices.[94] Nuwayhid and Werling[95] recently dem- Localisation of σ-1 receptors on the ER is in onstrated that σ-1 receptor agonists regulate perfect agreement with σ-1 receptors regulating NMDA-induced dopamine release from rat striatal Ca2+ signaling via inositol 1,4,5-trisphosphate (IP3) slices via the protein kinase C pathway. σ-1 receptor receptors on the ER.[47] σ-1 receptor agonists were agonists and neurosteroids, on the other hand, poten- found to potentiate IP3-induced Ca2+ mobilisation tiate NMDA-induced noradrenaline release from rat in a biphasic dose-dependent manner in a neuronal hippocampus slices.[41] It has also been shown, using cell line.[47] The regulation is mediated by the asso- in vivo microdialysis, that σ-1 receptor agonists ciation of the σ-1 receptor with cytoskeletal proteins increase spontaneous acetylcholine release in the frontal cortex.[96] In addition to its action at the ER, the σ-1 recep- Although the exact molecular action of the σ-1 tor can also modulate several physiological and cel- receptor remain unclear, the receptor appears to lular events on the plasma membrane (table II). The regulate neuronal excitability by modulating plasma receptor regulates ion channels such as K+ chan- membrane potentials and/or intracellular Ca2+ sig- nels,[56] NMDA receptors[57-62] and voltage-depen- naling. It should be emphasised that most of the dent Ca2+ channels.[47,63] It is suggested that the σ-1 pharmacological effects of σ-1 receptor ligands are receptor inhibits the K+ channel current by a direct ‘modulatory'. σ-1 receptor agonists did not cause coupling as a modulatory subunit.[56] Further re- Ca2+ mobilisation, neuronal firing and dopamine  2004 Adis Data Information BV. All rights reserved.
CNS Drugs 2004; 18 (5) Hayashi & Su release by themselves in the above-mentioned stud- pose that σ-1 receptors might be involved in regulat-ing the remodelling of neuronal membranes.[54,55,99] ies;[47,66,95] they exerted their modulatory actionwhen the IP3 receptor, K+ channel or NMDA chan- 2. Effects of σ-1 Receptor Ligands in
nel was activated by transmitters or depolarisa- Animal Models of Behaviour
tion[47,56,66,95] (also see review by Su and Hayashi[97]for details). Taken together, σ-1 receptors appear to σ-1 receptor ligands have been tested in several play an important role in the CNS as a modulator or animal models of behaviour. Actions of σ-1 receptor an amplifier of signal transduction in systems such ligands include: (i) improvement of memory and as NMDA channel activity, Ca2+ signalling and cognitive function; (ii) antidepressant-like actions; NGF-induced cell differentation.[97] These systems and (iii) modulation of psychostimulant-induced be- have recently been shown to be essential factors in the formation of neural plasticity.[98] Thus, we pro- 2.1 Drug-Induced Amnesia Table II. Modulatory pharmacological action of σ-1 receptor ligands
System/model effected It is well established that cholinergic and gluta- matergic (especially via the NMDA receptor sub- In vitro studies
type) neurotransmitter systems play a crucial role in Ion channel activity[47,56-64] Glutamate NMDA the neurophysiological processes underlying learn- ing and memory.[100,101] Selective σ-1 agonists have been shown to re- verse amnesia induced by acetylcholine muscarinic and nicotinic receptor antagonists in animals.[69,102] It is interesting that σ-1 receptor agonists including (+)pentazocine, (+)SKF-10047 and 1,3-di-o-tolyl- guanidine (DTG) exert an anti-amnesic action when Neuron firing[39,66-68] Glutamatergic (NMDA) administered either at pre-training, immediately neuron in hippocampus after training or before retention test time points of Serotonergic neuron in dorsal raphe nucleus mnemonic examinations.[69,102,103] These results sug- Dopaminergic neuron in gest that σ-1 receptor agonists can improve acetyl- choline-related cognitive processes encompassing all phases of memory formation: acquisition, con- Y-maze test and passive Improvedavoidance[39,40,49,67,69-72] solidation and retention.
Depression and stress Selective σ-1 agonists also improve amnesia in- duced by a NMDA receptor antagonist or by a Ca2+ channel antagonist.[70,71] Using different behavioural tests, Maurice et al.[70] demonstrated that σ-1 recep- Stress-induced colon tor agonists produce significant attenuation of short- PCP-induced cognitive and long-term memory disturbances induced by dizocilpine (MK-801). This action was blocked by Psychostimulant-induced Inhibited by NE-100, a σ-1 receptor antagonist.
Notably, in all behavioural tests for learning and memory, σ-1 receptor agonists again show a modu- conditioned place latory pharmacological action. They show anti-am- nesic action only when memory and cognition are Cocaine toxicity[85-88] impaired by chemicals that inhibit neural transmis- sion. By themselves, they do not further augment memory in normal animals. It is reported that σ-1 IP3 = inositol 1,4,5-triphosphate; PCP = phencyclidine.
receptor ligands also show beneficial effect against  2004 Adis Data Information BV. All rights reserved.
CNS Drugs 2004; 18 (5) σ-1 Receptors in Neuropsychiatric Disorders memory impairment induced by physiological pro- and dementia is unclear at present, σ-1 receptor cesses such as aging.[72] agonists may improve memory and cognition in σ-1 ligands may not cause the adverse effect, certain types of dementia.
such as peripheral cholinomimetic responses, thatare often associated with acetylcholinesterase inhib- 2.2 Depression and Anxiety itors (the current gold standard treatment for demen-tia).
Because σ-1 ligands improve amnesia induced The effects of σ-1 receptor ligands in animal by Ca2+, acetylcholine or NMDA channel blockers, models of depression have recently been investigat- intracellular Ca2+ appears to be a candidate as a ed. The immobility time in the mouse forced swim- common factor regulated by σ-1 receptors. This ming test was dose-dependently reduced by σ-1 possibility has been further investigated[104] and it receptor agonists.[73] Structurally diverse σ receptor has been found that σ-1 receptors regulate Ca2+ agonists such as (+)pentazocine, SA-4503 and release from intracellular Ca2+ storage sites.[47,53] igmesine (JO-1784) all decreased the immobility Furthermore, it has been shown that injections of time in the test.[73,74,111] This action was blocked by inhibitors of intracellular Ca2+ release into the brain the σ-1 receptor antagonist NE-100.
abolish the effects of σ-1 receptor agonists in beha- Neurosteroids such as pregnenolone sulphate and viour tests.[104] PB-008 act as σ-1 receptor agonists, although pro- Cognitive function depends partly on neuroster- gesterone acts apparently as a σ-1 receptor ant- oid levels, which are decreased by aging. It has been agonist.[3,40,47] Since sulphated neurosteroids act as shown that levels of pregnenolone sulphate are sig- reservoirs for the unsulphated neurosteroids in the nificantly lower in the hippocampus of aged (24- brain, their levels are much higher than those of month) than in young ( 3-month) male animals.[105] unsulphated forms.[33] Pregnenolone sulphate and Low levels of pregnenolone sulphate in the hippo- PB-008 have higher affinities for the σ-1 receptor campus are correlated with poor performance in than their unsulphated forms.[32] Therefore, their spatial memory tasks.[105] Central or systematic ad- concentrations in the brain may reach a sufficient ministration of PB-008 (dihydroepiandrosterone level to interact with σ-1 receptors under certain [DHEA] sulphate) and pregnenolone sulphate im- psychological states such as stress, anxiety and ag- proves/enhances mnemonic performances.[105] gression.[33] The interaction between the σ-1 recep- These actions of neurosteroids involve NMDA-de- tor and neurosteroids has been shown in the forced pendent processes, but have also been shown to be swimming test.[73,74,111] The above neurosteroids sig- blocked by selective σ-1 receptor antagonists.[40] nificantly decreased the immobility time in these Therefore, σ-1 receptors regulating cognitive func- studies, an effect that was blocked by NE-100 and tion may involve an interaction between neuroster- BD-1047, suggesting that certain neurosteroids ex- oids and NMDA receptors. A recent study demon- ert antidepressant actions by interacting with σ-1receptors.[73,74] strated that there is a general trend toward lowerlevels of neurosteroids in different brain regions of Extract of the flowering plant St John's wort individuals with Alzheimer's disease or aged nor- (Hypericum perforatum) is prescribed as an antide- mal subjects. The metabolism of PB-008 is also pressant in Germany. However, the mechanism of shown to decrease in these subjects.[106] A study the antidepressant action of St John's wort remains using post-mortem brains showed a 26% reduction unknown. Raffa[112] tested the binding of hypericin of [3H]DTG binding in the CA1 region of the hippo- (a major component of St John's wort) to 30 recep- campi in patients affected by Alzheimer's dis- tors or uptake sites that are suspected to be involved ease.[107] Some clinical studies suggest that hormone in the action of clinically used antidepressants. At replacement therapy using estrogen and PB-008 im- 1.0 µmol/L, hypericin inhibited less than 40% of proves cognitive function and may protect against specific binding at all receptors or uptake sites ex- age-associated memory decline.[106,108-110] Thus, al- cept acetylcholine muscarinic receptors and σ recep- though the relationship between the σ-1 receptor tors.[112] Hypericine (1.0 µmol/L) inhibits 48% of  2004 Adis Data Information BV. All rights reserved.
CNS Drugs 2004; 18 (5) Hayashi & Su [3H]DTG binding. Because the author used subtype- 2.3 Psychosis, Drug-Dependence nonselective ligands in his assay, it is unclear at present which subtype of σ receptor (1 or 2) binds tohypericine. The antidepressant action of hypericin in the forced swimming test was inhibited by a σ-1 Since σ-1 receptor ligands were originally expec- receptor antagonist.[75] Bennett et al.[113] systemical- ted to represent a new class of antipsychotics, a ly evaluated all articles on hypericin identified from substantial number of experiments have been per- a database and suggested that the σ receptor is a formed to examine the potential involvement of σ-1 potential site of action for hypericin.
receptors in schizophrenia using animal models.
Because the pharmacological effect of σ-1 recep- Amphetamine and PCP are frequently employed as tor ligands is typically modulatory, it is reasonable the animal model of schizophrenia. Amphetamine to propose developing compounds that possess a mimicks acute positive symptoms of schizophrenia,such as delusion and hallucination. Methamphetam- high affinity for both σ-1 receptors and other recep- ine and apomorphine are also known to induce simi- tors that are known to be related to certain pathologi- lar effects. Because PCP causes not only acute psy- cal states such as depression. A newly synthesised chosis mimicking positive symptoms but also long- antidepressant OPC-14523 has a high affinity for lasting psychosocial dysfunction similar to the nega- both σ-1 receptors (47–56 nmol/L) and serotonin tive symptoms of schizophrenia, PCP-induced psy- 5-HT1A receptors (2.3 nmol/L).[76] A single oral chosis is suggested to be a suitable model for schizo- administration of OPC-14523 produced a marked antidepressant-like effect in the forced swimmingtest, whereas fluoxetine and imipramine required at Some putative σ-1 receptor antagonists (e.g.
least four days of repeated administration to show BMS-181100 [BMY-14802]) inhibit methamphet- the same activity.[76] This potent antidepressant-like amine-induced locomotor activity and apomor- action of OPC-14523 can be mimicked by combined phine-induced stereotypy.[115] However, highly se- administration of σ-1 and 5-HT σ-1 antagonists such as NE-100 and MS-377 do not affect locomotor activity induced by an injec-tion of amphetamine.[24,25,81] Some of these experi- ments used σ receptor ligands at high doses (>20mg/kg);[24] therefore, the inhibitory effect seen on σ-1 ligands also exert anxiolytic action in animal psychostimulant-induced locomotor activity may behavioural tests.[78] Animals exhibit a marked sup- not be solely due to interaction with the σ-1 recep- pression of motility when they are placed in the tor. In fact, the action of σ-1 ligands on amnesia (see same environment in which they had previously section 2.1) is usually seen at doses below 1 mg/kg, received an electric footshock (conditioned fear and the effect usually disappears at higher doses (> 3 stress). (+)SKF-10047 reversed the conditioned fear mg/kg).[70] Selective antagonism of dopamine D2 stress and this effect was blocked by NE-100.[78] receptors seems to be more effective in attenuating However, this anxiolytic action was not seen with locomotion and stereotypy induced by the acute (+)pentazocine and DTG.
administration of psychostimulants. Taken together, Gue et al.[79,80] reported that the σ-1 receptor the data on the direct involvement of σ-1 receptors agonist igmesine attenuates an increase of colonic in schizophrenia, especially acute psychotic symp- spike bursts induced by conditioned fear stress or toms, is equivocal.
corticotropin releasing hormone. Their findings are NE-100 is highly selective for σ-1 receptors and relevant with regard to gastrointestinal tract disor- is the most well-defined functional σ-1 receptor ders that are frequently seen in anxiety and mood antagonist.[24] NE-100 does not affect behaviours induced by amphetamine, but inhibits several types More studies using structurally different σ-1 of behaviour induced by PCP.[24] The order of inhib- ligands may confirm the possible involvement of the iting potencies on PCP-induced head weaving by σ-1 receptor in anxiety.
σ-1 receptor antagonists (NE-100 > haloperidol >  2004 Adis Data Information BV. All rights reserved.
CNS Drugs 2004; 18 (5) σ-1 Receptors in Neuropsychiatric Disorders BMS-181100 > Dup-734) correlates well with their agonists, indicating the potential involvement of σ-1receptors in cocaine-induced toxicity.[88] affinities for σ-1 receptors.[24] PCP-induced beha-viour is insensitive to selective D2 receptor antagon- Recently, the σ receptor antagonists BD-1047 ists, but can be attenuated by very low doses of and LR-172 were shown to inhibit cocaine-induced NE-100 (<0.1 mg/kg).[24] In addition, NE-100 alone locomotor activity.[86] Both compounds possess sim- did not cause any extrapyramidal symptoms. Selec- ilar high affinities for σ-1 receptors. However, tive σ-1 receptor agonists such as (+)pentazocine, at LR-172, which possesses much greater affinity at low doses that caused no behavioural activity, en- σ-2 receptors, was a more potent inhibitor than hanced the behavioural effect of dizocilpine, and BD-1047 against cocaine-induced locomotor ac- this enhancement was blocked by NE-100 (0.01–0.1 tivity.[86] These data may suggest the involvement of mg/kg).[24] Thus, it is very likely that one potential σ-2 receptors in this action.
site of action of the σ-1 receptor is the regulation of The affinity of cocaine for σ-1 receptors is about ion channels coupled to NMDA receptors. A dys- 2 µmol/L.[118] The intracellular concentration of co- function of glutamatergic transmission, specifically, caine in the brain of cocaine abusers might not reach in the frontal cortex is implicated in schizo- a sufficient level to occupy σ-1 receptors on the ER.
phrenia.[114,116] σ-1 receptor ligands may thus affect Romieu et al.[84] reported that conditioned place certain schizophrenic symptoms that are related to a preference induced either by cocaine or a selective dysfunction of glutamatergic transmission.
dopamine transporter inhibitor without any σ-1 re-ceptor affinity is inhibited by a selective σ-1 recep- It has been shown that the microinjection of σ tor antagonist, suggesting that σ-1 receptors may receptor ligands, including DTG and play a role downstream of dopaminergic transduc- (+)SKF-10047, into the red nucleus causes dystonia tion. Further studies are required to clarify the mech- in animals.[117] Antipsychotics lacking affinity for σ anism by which σ-1 receptors may be involved in receptors such as clozapine fail to induce this move- cocaine abuse.
ment disorder. Interestingly, the microinjection of Ujike et al.[82,83] reported that putative σ receptor these σ ligands into the substantia nigra produces antagonists, at doses per se not affecting spontan- vigourous contralateral circling behaviour at ex- eous locomotor activity, block the development of tremely low doses. These data suggest the possibili- behavioural sensitisation induced by cocaine and ty that σ receptors are involved in the motor adverse methamphetamine. This action of σ receptor ant- effects of antipsychotics. The σ ligand-induced agonists was confirmed by other researchers using movement disorders seem to involve both σ-1 and the selective σ-1 antagonist MS-377.[81] σ-2 subtypes.[85] This information will be importantwhen the safety of σ-1 receptor ligands is evaluated in clinical trials.
Several reports indicate that σ-1 receptor ago- nists can inhibit opioid-induced analgesia.[89-91] As 2.3.2 Drug Dependence
shown in figure 1, σ-1 receptors are enriched in thespinal cord and peripheral nerves where opioid re- Recently, the involvement of the σ-1 receptor in ceptors are enriched. σ-1 receptors and ligands may the pharmacological action of cocaine has been in- thus regulate opiate receptor activities at these loci.
tensively investigated. Because cocaine has a mod-erate affinity for σ-1 receptors,[118] it is suggested 3. Potential Therapeutic Targets of
that certain actions of cocaine, inducing its toxic Selective σ-1 Receptor Ligands
effects, may be attributed to its direct interactionwith σ-1 receptors.[99] 3.1 Schizophrenia Matsumoto and colleagues[86-88] clearly demon- strated that novel σ receptor antagonists at low The demonstration that benzomorphans, such as doses (1 mg/kg) significantly inhibit convulsions SKF-10047, produce ‘canine delirium' and psycho- and lethality induced by a toxic dose of cocaine. The sis in dogs[1] led to the proposal that σ-1 receptors toxicity of cocaine was potentiated by σ-1 receptor mediate these effects. Binding studies using  2004 Adis Data Information BV. All rights reserved.
CNS Drugs 2004; 18 (5) Hayashi & Su [3H]SKF-10047 and (+)[3H]-3-PPP identified an BPRS scores were ≥35. In a single-blind trial, treat- abundance of σ receptors in the brain.[7,10-13] An ment with BMS-181100 (500–1500mg twice daily important role of σ receptors in schizophrenia is also up to a maximum of 3000 mg/day) for 4 weeks in 28 suggested by the high affinity of many established patients was not associated with any improvements antipsychotic drugs for σ receptors.[7] However, in in BPRS and CGI score.[28] The most frequent ad- the early reports on benzomorphan-induced psycho- verse effect was mild to moderate sinus tachycardia.
sis in humans, very high dose of pentazocine were Elevations in creatine phosphokinase (CPK) levels, usually administered.[5,6] In most case, a mixture of agitation and insomnia were seen in some patients.
both (+) and (–) isomers were given.[5,6] Considering There are a number of issues associated with that these benzomorphans have moderate to high these two trials[27,28] that need to be considered: (i) affinities for the PCP site,[9] the psychotomimetic the functional activity of the ligands and their selec- action of benzomorphans might be mainly attributed tivity for the σ-1 receptor were not fully character- to their interaction with the PCP site. In fact, recent- ised via in vivo and in vitro assays; (ii) only schizo- ly synthesised highly selective σ-1 receptor agonists phrenic patients in the acute psychotic phase were do not have any psychotomimetic activity in animal studied; (iii) the subclass of symptoms was assessed studies,[76,102] negating a direct relationship between only using the BPRS, which mainly reflects the activation of σ-1 receptors and acute psychosis.
degree of positive symptoms; (iv) the duration of Binding assays using post-mortem brains of schizo- evaluation might not have been long enough (evalu- phrenic patients[119,120] and association studies of ation longer than 4 weeks is usually required for polymorphism of σ-1 receptor genes in schizo- examining changes in negative symptoms); and (v) phrenic patients[121,122] have been performed. How- an effective dose might not have been used in the ever, results vary and are not conclusive.
BMS-181100 study[28] (too high in this trial).
Some σ receptor ligands have been tested in Modell et al.[31] tested the effect of eliprodil clinical trials (see table I). Rimcazole (BW-234U) (SL-82.0715), a potent σ-1 receptor ligand, on was the first σ receptor ligand to be tested in a schizophrenia in an open-label, dose-ranging study.
clinical trial. After a 1-week placebo washout This compound exacerbated acute psychotic symp- period, rimcazole was administered for 4 weeks to toms in some patients in an earlier study,[125] as was 11 patients with schizophrenia who were experienc- seen in the rimcazole and BMS-181100 stud- ing an acute exacerbation of symptoms.[27] Subjects ies.[27,28,123,124] Therefore, subjects with the diagnosis were assigned on a double-blind, randomised basis of residual-type schizophrenia with a predominant to one of four flexible dosing treatment regimens negative symptomatology (score of >28 on the nega- (rimcazole 20–80 mg/day, rimcazole 100–400 mg/ tive subscale of the Positive and Negative Syndrome day, chlorpromazine 400–1600 mg/day or placebo).
Scale [PANSS]) were included in this study. After a Rimcazole was not associated with any significant 1- to 2-week washout period, patients received improvement in the Brief Psychiatric Rating Scale eliprodil for 4 weeks (2.5 mg/day for the first week, (BPRS) and Clinical Global Impressions (CGI) then up to 75 mg/day). Although the number of scores. However, it did not show any neurological subjects was limited (n = 10), a significant reduction adverse effects. Although rimcazole selectively of scores in negative symptoms, but not in positive binds to σ-1 receptors, it is a weak antagonist (inhi- symptoms, according to the PANSS was found.
bition constant [Ki] = 2.4 µmol/L).[24] In contrast to Panamesine (EMD-57445), a potent σ receptor these results, in earlier open studies, rimcazole was ligand with antidopaminergic activity, was shown to found to cause improvement of negative symptoms improve both positive and negative symptoms in an such as depression and anergia, but a worsening of open clinical trial.[29,30] In this study, panamesine acute positive symptoms.[123,124] (15mg on day one, 30mg on day two, 45mg on day BMS-181100, a relatively selective and potent three and 60mg from day four onwards) was admin- σ-1 receptor antagonist, was also tested in patients istered to 12 schizophrenic patients for 4 weeks, and with acute exacerbation of schizophrenic symptom- effects were assessed by both the BPRS and the atology. Subjects were included in this study if their PANSS. Statistical analyses showed a significant  2004 Adis Data Information BV. All rights reserved.
CNS Drugs 2004; 18 (5) σ-1 Receptors in Neuropsychiatric Disorders reduction of PANSS scores related to both positive significant importance in depression.[36,37] Several and negative symptoms after 3 weeks of panamesine studies have also suggested the involvement of use. However, panamesine induced mild dyskinetic neurosteroids in premenstrual dysphoric disorder movements in 5 of the 12 patients. It needs to be (PMDD)[128] and attention-deficit hyperactivity dis- further characterised whether these effects, or a part of them, are mediated by a direct interaction with In patients with major depression, neurosteroid σ-1 receptors, because a metabolite of the drug has levels in the CSF are lower than in control subjects potent antidopaminergic activity.[126] and these levels normalise after successful treatment Taken together, these results suggest that selec- with antidepressants.[36,37] SSRIs have been shown tive σ-1 receptor antagonists appear to have thera- to normalise levels of allopregnenolone in a seroto- peutic effects on some symptoms of schizophrenia nin-independent manner.[37] It is well known that but not acute positive symptoms. As mentioned in plasma cortisol levels are increased in depressed section 2.3, selective σ-1 receptor antagonists may patients,[36,130] and that PB-008 regulates cortisol not affect acute psychosis mediated by the activation levels.[131] Some studies found significantly higher of dopaminergic transduction, but can inhibit PCP- cortisol/PB-008 ratios in depressed patients com- induced behaviours in animals. So far, no anti- pared with controls.[36,132] Administration of PB-008 psychotic which manipulates glutamatergic neural has been shown to reduce plasma cortisol levels.[132] transmission is available. Therefore, the beneficial The important neurosteroid-targeted receptors in effect of σ-1 receptor ligands might be seen when the brain include the GABAA, NMDA and σ-1 they are used to target symptoms of schizophrenia receptors.[33,36] PB-008 interacts with σ-1 receptors that are mediated predominantly via glutamatergic as an agonist and exerts antidepressant-like action in systems rather than dopaminergic systems. Thus, an animal model of depression.[73,74] The molecular σ-1 receptor ligands may affect negative symptoms mechanism underlying this action of σ-1 receptors is of schizophrenia, which are hypothesised to be me- unclear at present. However, it is very likely that the diated, at least partly, by glutamatergic transmis- σ-1 receptor plays an important role in the biologi- cal action of neurosteroids (or neuroactive steroids) At low doses, psychostimulants exacerbate psy- in depression. Orally administered neuroactive ster- chosis in patients with remitting schizophrenia.
oids may not result in an increase in levels in the Long-term drug abusers sometimes show psychotic brain due to a rapid metabolism. Selective σ-1 re- symptoms similar to those seen in schizophrenia ceptor agonists may act in a complementarily fash- when taking a low dose of psychostimulants or even ion to neurosteroids in the brain.
when stressed. Therefore, the behavioural sensitisa- So far, the only reports of the clinical use of a σ-1 tion to psychostimulants has been used as a model of receptor ligand as an antidepressant are of igmesine.
schizophrenia, especially for studies of deterioration In an open trial,[26] igmesine showed a significant and exacerbation of manifested symptoms.[127] Judg- improvement in 31 severely depressed inpatients. A ing from the behavioural sensitisation data in ani- double-blind placebo-controlled study comparing mals,[81-83] σ-1 receptor antagonists might have a igmesine 25 and 100 mg/day with fluoxetine 20 mg/ prophylactic effect in preventing the recurrence of day in 348 patients with major depressive disorder schizophrenia. However, so far, no clinical study was performed in three different countries (UK, regarding this issue has been performed.
Poland and the Czech Republic). Although no sig-nificant effect was found comparing total samples, a 3.2 Depression and Senile Dementia subset of patients receiving igmesine 25 mg/day It has been established that abnormalities of sero- from UK sites (n = 263) showed a 3 point greater tonergic and noradrenergic neural transmission are decrease in total Hamilton Depression Rating Scalescore than the placebo group (p < 0.05).[26] involved in the pathophysiology of depression.
However, recent studies have also demonstrated the To date, there have been no reports of the use of a involvement of neurosteroids in depression.[36] Al- σ-1 receptor ligand to treat dementia. According to lopregnenolone and PB-008, in particular, are of aforementioned recent preclinical studies, however,  2004 Adis Data Information BV. All rights reserved.
CNS Drugs 2004; 18 (5) Hayashi & Su it is highly possible that σ-1 receptor agonists may Pathological state(e.g. depression, cognition impairment) augment cognitive functions and improve mood inpatients with psychiatric disorders. Because the ac-tion of σ-1 receptor ligands is mainly modulatory, σ-1 receptor ligands are expected to restore the existing (but functionally declining) neural trans-mission.
Because the σ-1 receptor is involved in higher- ordered brain functions such as memory, cognition and mood, it may be involved in the development of neuronal plasticity. The pathophysiology of certain neuropsychiatric disorders, such as drug dependence Fig. 2. A hypothetical scheme of the ‘modulatory' action of σ-1
and depression, has been shown to involve neural receptor ligands. σ-1 receptors may possess innate biological ac- plasticity that may be related to dentrite outgrowth tivity. In the normal brain, the activity of σ-1 receptors would bemaintained within a sufficient range (shaded area) for regulating and synapse formation.[92,133-135] Thus, σ-1 receptor neurophysiological functions. The factor that maintains the activity ligands might show therapeutic actions by affecting of σ-1 receptors is unknown at present. If neuronal activity de- the remodelling of neural membranes, as we have creases due to certain pathological states or influences from exoge- nous compounds, σ-1 receptors would become hypoactive (line 2).
σ-1 receptor agonists at appropriate doses may act as modulators A unique pharmacological feature of selective to compensate for the reduced activity of the receptor (line 1). σ-1 σ-1 receptor ligands is their ‘modulatory' action.
antagonists would eliminate the augmentation of the σ-1 receptor For example, in in vitro studies, σ-1 receptor ligands activity induced by σ-1 agonists (line 3). At excessive doses of anagonist, the effects of σ-1 receptors could disappear (shifting from did not affect intracellular Ca2+ levels by them- line 1 to 2) as has been shown in in vivo and in vitro studies.[39,47,65] selves, but potentiated IP3-induced Ca2+ mobilisa-tion.[47] In behavioural studies examining mnemonic tors become hypoactive (or hyperactive) under cer- processes, σ-1 receptor agonists showed effects only tain pathological states, σ-1 ligands might compen- when memory was impaired.[70] sate for (or normalise) the biological activity of the We do not know exactly how σ-1 receptor protein. This hypothesis should be further addressed ligands exert this modulatory action, but we propose in the future.
here a hypothetical scheme of this action (figure 2).
When dopamine receptor ligands are administered Potential therapeutic targets of σ-1 ligands may to normal animals, agonists per se induce physiolog- include depression and senile dementia. The action ical or behavioural alterations by activating the re- of σ-l ligands in these diseases might be, at least in ceptors. Conversely, antagonists induce certain ac- part, related to an effect on neurosteroids via an tions by displacing endogenous dopamine. These unknown mechanism. The effects of σ-1 receptor actions are not seen with σ-1 receptor ligands. Both ligands in schizophrenia seem to be equivocal, al- σ-1 receptor agonists and antagonists apparently though their effects on certain symptoms (e.g. nega- show no effects when administered to normal ani- tive symptoms, depressive symptoms and prophy- mals (see section 2.1). σ-1 receptor proteins per se laxis) warrant further investigation.
may possess certain unknown biological activity, Because of their modulatory action, σ-1 ligands even in the absence of ligands. However, the exis- may be active only in patients who have neurop- tence of endogenous σ-1 receptor ligands does not sychiatric diseases. Therefore, they might be expec- explain the existing biological activity of σ-1 recep- ted to show only minimal adverse effects. Also tors, because σ-1 receptor antagonists lack pharma-cological effects in normal subjects. σ-1 receptor because of their unique action, it is reasonable to ligands may merely work as a modulator of the propose developing compounds that possess a high existing activity of σ-1 receptors. When σ-1 recep- affinity for both σ-1 receptors and other receptors  2004 Adis Data Information BV. All rights reserved.
CNS Drugs 2004; 18 (5) σ-1 Receptors in Neuropsychiatric Disorders sigma receptor. Biochem Biophys Res Commun 1997; 241: which are known to be involved in certain patholog- ical states such as depression.
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CNS Drugs 2004; 18 (5)

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