Mini-Review • DOI: 10.2478/s13380-012-0030-0 • Translational Neuroscience • 3(3) • 2012 • 294-299 Translational Neuroscience

Roles of σ1 ReceptoRs

Jun Toyohara*, In the mechAnIsms Muneyuki Sakata, Kiichi Ishiwata of ActIon of cns dRugs Positron Medical Center, Abstract

Tokyo Metropolitan Institute of Gerontology, Accumulating evidence suggests that σ1 receptors play a role in the mechanisms of action of some therapeutic 1-1, Naka, Itabashi, Tokyo, 173-0022, Japan drugs, such as the selective serotonin reuptake inhibitors (SSRIs), donepezil, and ifenprodil. Among the SSRIs, fluvoxamine, a potent σ1 receptor agonist, has the highest affinity for σ1 receptors, while donepezil and ifenprodil

also show high affinity for1 σ receptors. These drugs affect neuronal plasticity indicated by potentiation of nerve-growth factor (NGF)-induced neurite outgrowth in PC12 cells. Furthermore, phencyclidine (PCP)-induced cognitive impairment, associated with animal models of schizophrenia, is significantly improved by sub-chronic administration of fluvoxamine and donepezil. These pharmacological actions are antagonised by treatment with

the selective σ1 receptor antagonist NE-100. Positron emission tomography (PET) with the σ1 specific ligand carbon-11-labelled 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine ([11C]SA4503) indicated that

fluvoxamine and donepezil can bind to σ1 receptors in the healthy human brain in a dose-dependent manner.

These findings suggest that 1σ receptors may be involved in the mechanisms of action of some therapeutic drugs. Keywords

• σ1 receptor • Fluvoxamine • Donepezil • Ifenprodil • SSRI • Neuronal plasticity • Positron emission tomography Received 13 July 2012 accepted 17 July 2012 © Versita Sp. z o.o.

Abbreviations the effects of a prototypical opioid agonist, receptors, PGMRC1 sites were localised in the SKF10,047 (N-allylnormetazocine), were ER and mitochondria.

AChE - acetylcholinesterase independent from those of other opioid Endogenous ligands for the σ1 and σ2 AD - Alzheimer’s disease receptor agonists [1]. It was later determined receptors have not been fully identified,

CNS - central nervous system that σ receptors have unique binding sites and those for the σ1 receptor were first EBP - emopamil binding protein that are different from those of other opioid proposed to be neurosteroids, including

ER - endoplasmic reticulum receptors, and at least two subtypes (σ1 and pregnenolone sulphate and progesterone [7].

ifenprodil - 4-[2-(4-benzylpiperidin-1-yl)-1- σ2) were classified based on pharmacological The endogenous hallucinogenic trace amine

hydroxypropyl]phenol criteria [2]. In 1996, the σ1 receptor was N,N-dimethyltryptamine was recently found

NE-100 - 4-methoxy-3-(2-phenylethoxy)- successfully cloned and characterised as to be a potent endogenous ligand for the σ1 N,N-dipropylbenzeneethanamine a protein of 233 amino acids with two receptor [8].

NGF - nerve growth factor transmembrane domains [3]. Although the σ1 The σ1 and σ2 receptors display different NMDA - N-methyl-D-aspartate receptor is not homologous to any mammalian tissue distributions and distinct physiological PCP - phencyclidine protein, it shows a 30% overlap with yeast D8- and pharmacological profiles in the central

PET - positron emission tomography D7 sterol isomerase, also known as emopamil- and peripheral nervous systems [9]. The σ1

PGRMC1 - progesterone receptor membrane binding protein (EBP) [4]. The σ2 receptor has receptors are widely distributed in the central component 1 yet to be cloned. nervous system (CNS) and in peripheral

SA4503 - 1-[2-(3,4-dimethoxyphenyl)ethyl]- The σ1 receptors have been shown to act as tissues [10]. Peripherally, both subtypes are 4-(3-phenylpropyl)piperazine ligand-regulated molecular chaperones in the overexpressed in rapidly proliferating cells, SSRI - selective serotonin reuptake inhibitor endoplasmic reticulum (ER) [5]. It is the first such as those in various types of cancer, and the

VT - total distribution volume. molecular chaperone in which the activity was functional roles of the receptors, especially σ2, found to be regulated by synthetic compounds have been the focus of tumour imaging studies

Introduction in a clear agonist-antagonist manner [5]. Very [11]. In the CNS, the σ1 receptor may function

recently, the putative σ2 binding site was as a modulator of signal transduction through The σ receptors were initially categorised identified as progesterone receptor membrane glutamatergic transmitter systems mediated

as a subtype of opioid receptors, because component 1 (PGRMC1) [6]. Similar to the σ1 by N-methyl-D-aspartate (NMDA) receptors.

* E-mail: [email protected]

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The σ1 receptor has been implicated in cellular or paroxetine, significantly potentiated nerve administration of fluvoxamine (20 mg/kg/day), differentiation [12,13], neuroplasticity [14,15], growth factor (NGF)-induced neurite outgrowth but not sertraline (10 or 20mg/kg/day) [23]. The neuroprotection [16,17] and cognitive function in PC12 cells in a concentration-dependent effect of fluvoxamine on PCP-induced cognitive in the brain [18]. manner [22]. The potentiation by fluvoxamine deficits was antagonised by co-administration

The σ1 agonists show anti-amnesic was significantly blocked by co-administration of the selective σ1 receptor antagonist NE-100. and neuroprotective effects [19], and are of 4-methoxy-3-(2-phenylethoxy)-N,N- These findings suggest that agonistic activity therefore attractive, novel targets for the dipropylbenzeneethanamine (NE-100), of fluvoxamine at σ1 receptors plays a role in treatment of neuropsychiatric diseases suggesting that the neuroplastic actions the active mechanisms of fluvoxamine on PCP-

(schizophrenia, depression and cognition) of fluvoxamine are mediated through σ1 induced cognitive deficits in mice. In these and neurodegenerative diseases, such as receptors. Furthermore, Hashimoto et al. reports, sertraline, which also has high affinity ischemic stroke and Alzheimer’s disease (AD). reported that phencyclidine (PCP)-induced for σ1 receptors, did not show any enhancement Several CNS drugs show high to moderate mouse cognitive deficits, as measured in the of neurite outgrowth and cognition. One affinities for σ1 receptors, including selective novel object recognition test, were significantly possible explanation may be differences in serotonin reuptake inhibitors (SSRIs) improved by subsequent sub-chronic (2 weeks) pharmacology (agonist vs. antagonist) between (fluvoxamine), acetylcholinesterase (AChE) inhibitors (donepezil) and cerebral vasodilator Table 1. Affinities of selective serotonin reuptake inhibitors (SSRIs) at1 σ receptors in the rat brain (modified from reference [21]). (ifenprodil). These compounds can influence cognitive functions both via their primary Ki (nM) Ki ratio Compounds Chemical structure targets and by activating σ1 receptors in the σ1 σ2 σ2/σ1 CNS. Furthermore, these compounds affect neuronal plasticity, a process implicated in the O pathophysiology of disease of the CNS, such as F major depressive disorder, schizophrenia and Fluvoxamine 36 8439 234 F AD. This article presents a review and discussion NO F of the roles of σ1 receptors in the mechanisms of action of several therapeutic drugs. H2N

σ1 receptors and ssRIs Sertraline 57 5279 93 Cl NH SSRIs have been used as therapeutic drugs for depression. Although the mechanisms of Cl action of all SSRIs share the function of blocking F serotonin transporters, their pharmacological F effects are quite heterogeneous [20]. Inhibition (±)Fluoxetine 240 16100 68 F of serotonin reuptake and the consequent N O increase in serotonin availability are responsible H for the relief of depressive symptoms. On F the other hand, trans-synaptic effects such as modulation of signalling cascades, gene expression processes, and neuroplasticity are Citalopram 292 5410 19 N also important in the mechanism of action of antidepressants. These secondary properties of O the SSRIs may contribute to the differences in N efficacy and tolerability between members of the class. O Narita et al. reported that some SSRIs possess O high to moderate affinity for σ1 receptors [21]. The HN O Paroxetine 1893 22870 12 rank order of potency of SSRIs for σ1 receptor is as follows: fluvoxamine > sertraline > fluoxetine > citalopram >> paroxetine (Table 1). Nishimura F et al. reported that fluvoxamine, but not sertraline

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these SSRIs at σ1 receptors. Another possibility countries, including Japan and France (Table 3). in PC12 cells in a concentration-dependent is that other pharmacological activities of Ifenprodil binds to NMDA receptors as well manner [33]. In contrast, the a1 adrenergic sertraline may mask the effects of σ1 receptor as a1 adrenergic receptors and σ receptors, receptor antagonist, prazosin, and the NMDA agonism. suggesting a possible role of σ receptors in receptor NR2B antagonist, (aR,bS)-a-(4- Although less well defined, the clinical the mechanism of the neuroprotective action hydroxyphenyl)-b-methyl-4-(phenylmethyl)- effect of fluvoxamine is also consistent with of ifenprodil [30-32]. Ishima and Hashimoto 1-piperidinepropanol (Ro 25-6981), did not

σ1 receptor agonism. Iyo et al. reported a case reported that ifenprodil significantly alter NGF-induced neurite outgrowth [33]. The that demonstrated the efficacy of fluvoxamine potentiated NGF-induced neurite outgrowth potentiation by ifenprodil was significantly (50 mg/day), but not paroxetine (20 mg/day), on cognitive deficits in a schizophrenic patient Table 2. Affinities of acetylcholinesterase (AChE) inhibitors for σ receptors in guinea pig brain (modified from reference [25]). treated with risperidone (no affinity for1 σ receptors) [24].

IC50 (nM) ratio Compounds Chemical structure σ* AChE AChE/σ σ1 receptors and donepezil O H Donepezil, an AChE inhibitor, is the most widely N TAK-147 3.83 51.2 13.4 prescribed drug for AD. In 1999, Kato et al. N reported that donepezil binds to σ1 receptors with high affinity in the brain, suggesting a role CH3 of σ1 receptors in the mechanisms of action of H N O donepezil (Table 2) [25]. Donepezil 14.6 21.5 1.5 O In vitro studies demonstrated that donepezil, O but not another AChE inhibitor physostigmine H3C (also known as eserine), significantly NH potentiated NGF-induced neurite outgrowth 2 in PC12 cells in a concentration-dependent Tacrine 6090 153 0.03 manner, and that the effect of donepezil N could be antagonised by NE-100 [26]. This potentiation effect of donepezil is unaffected O CH by cholinoceptor antagonists (mecamylamine, H 3 scopolamine) or cholinomimetic drugs Physostigmine >100000 125 <0.001 N H3C O CH3 (nicotine, carbachol) [27]. CH3 CH3 Donepezil was found to have a protective effect against amyloid b25-35 peptide-induced *IC for [3H]1,3-di(2-tolyl)guanidine binding site (σ and σ ). neurotoxicity in mice [28]. This effect of 50 1 2 donepezil was antagonised by the σ1 receptor antagonist N-[2-(3,4-dichlorophenyl)ethyl]- Table 3. Affinities of ifenprodil and its analogue eliprodil at σ receptors in the rat brain (modified from reference N-methyl-2-(dimethylamino)ethylamine [32]). (BD-1047). Furthermore, donepezil, but not

Ki (nM) Ki ratio physostigmine, significantly improved PCP- Compounds Chemical structure σ σ σ /σ induced cognitive impairments in mice, and 1 2 2 1 the effect of donepezil was antagonised by OH co-administration of NE-100 [29]. In summary, Ifenprodil 13 1.89 6.9 it is likely that σ1 receptors are involved N in the mechanism of the neuroprotective OH pharmacological action of donepezil. Cl

σ1 receptors and ifenprodil Eliprodil 132 634 4.8 F N Ifenprodil (Cerocral®) has been used as a OH cerebral vasodilator in a limited number of

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blocked by co-administration of NE-100, but serotonin transporters in healthy subjects after patients after oral administration of donepezil not of the σ2 receptor antagonist, (±)-tropanyl a single oral administration of fluvoxamine (3, 5 or 10 mg) [41-43]. It was reported that the

2-(4-chlorophenoxy)butanoate (SM-21). These (50 mg) [39]. These results suggest that, in IC50 values of donepezil for σ1 receptors and results suggest that the neuroplastic actions of therapeutic doses, fluvoxamine binds to σ1 AChE were 14.6 nM and 21.5 nM, respectively ifenprodil are mediated through σ1 receptors. receptors as well as serotonin transporters in [25]. Taken together, these findings suggest Interestingly, the ifenprodil analogue, eliprodil, the human brain, and this may be involved in that, in therapeutic doses, donepezil not only a neuroprotective drug with a high affinity the mechanism of action of fluvoxamine. inhibits AChE, but also binds to σ1 receptors in agonist action at σ1 receptors (Table 3), Furthermore, Ishikawa et al. reported that the human brain. It is therefore possible that strongly promotes myelination in neuron- a single administration of donepezil (5 or 10 σ1 receptors are involved in the mechanism of oligodendrocyte co-cultures [34]. Taken mg) dose-dependently decreased the [11C] the pharmacological action of donepezil in the together, this data suggest that σ1 receptor SA4503 binding in the human brain (Figure 2), human brain. activation by σ1 agonists is important for and the σ1 receptor occupancy rates reached Toyohara et al. recently evaluated the in vivo neuronal differentiation. approximately 75% [40]. Several studies blocking effects of ifenprodil on brain σ1 Recently, Kishimoto et al. reported that have demonstrated moderate inhibition receptors with [11C]SA4503 in mice [44]. They ifenprodil was effective in treating emotional (~20% – 40%) of AChE in the brains of AD found that the brain uptake of [11C]SA4503 incontinence in patients with vascular dementia, and flashbacks in female post- traumatic stress disorder patients with a history of childhood sexual abuse [35]. To our knowledge, this represents the first demonstration of a beneficial effect for ifenprodil in these groups of patients. With its high affinity for both NMDA and1 σ receptors, it is likely that ifenprodil acts on these receptors to alleviate emotional incontinence as well as flashbacks in these patients. Further large-scale clinical studies are needed to further confirm this initial finding.

measurement of σ1 receptor occupancy in the living human brain

Positron emission tomography (PET) is the most effective technique to estimate 11 Figure 1. Total distribution volume (VT) images of [ C]SA4503-PET before and after a single oral administration of receptor occupancy rates of drugs in the an SSRI. The upper pair represents VT images at baseline (left) and at paroxetine (20 mg)-loading (right) in the same subject. The lower pair shows V images at baseline (left) and fluvoxamine (200 mg) loading human brain [36]. Carbon-11-labelled T (right) in another subject. 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3- phenylpropyl)piperazine ([11C]SA4503) is a clinically available PET ligand for σ1 receptors in the human brain [37]. Using [11C]SA4503-PET, Ishikawa et al. reported that a single administration of a wide range of doses of fluvoxamine (50 – 200 mg, to achieve > 50% occupancy rates), but not of paroxetine (20 mg, which is thought to be an equivalent dose to 75 mg of fluvoxamine), dose-dependently decreased the [11C]SA4503 binding in the human brain (Figure 1), and the σ1 receptor occupancy rates reached approximately 60% [38]. Suhara et al. reported 11 a high occupancy rate (approximately 80%) for Figure 2. Representative VT images of [ C]SA4503-PET before and after a single oral administration of donepezil (10 mg) in a healthy subject. Left: image at baseline; right: image after donepezil (10 mg) loading.

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was dose-dependently decreased by co- Synthetic compounds that enable Acknowledgements administration of ifenprodil. The full block rate pharmacological manipulations of these brain of ifenprodil was the same as that of SA4503. functions may be potential candidates for the This work was supported by Grants-in Aid It is of great interest to determine whether or next generation of CNS drugs. The σ receptor for Scientific Research (B) No. 22390241 not ifenprodil binds to σ1 receptors in the living ligands are expected to serve as the next and Challenging Exploratory Research No. human brain. family of psychotherapeutic drugs [10,45-48]. 23659605 from the Japan Society for the As discussed above, several CNS drugs bind Promotion of Science (to Jun Toyohara). There conclusions to σ1 receptors that are involved in enhancing were no other potential conflicts of interest neuroplasticity and cognitive function. The relevant to this article. Synaptogenesis and neuronal plasticity should unique properties of these CNS drugs may be be important in future drug development. explained by this potent σ1 receptor agonism.

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