Pharmacology and Therapeutic Potential of Sigma1 Receptor Ligands E.J
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central 344 Current Neuropharmacology, 2008, 6, 344-366 Pharmacology and Therapeutic Potential of Sigma1 Receptor Ligands E.J. Cobos1,2, J.M. Entrena1, F.R. Nieto1, C.M. Cendán1 and E. Del Pozo1,* 1Department of Pharmacology and Institute of Neuroscience, Faculty of Medicine, and 2Biomedical Research Center, University of Granada, Granada, Spain Abstract: Sigma () receptors, initially described as a subtype of opioid receptors, are now considered unique receptors. Pharmacological studies have distinguished two types of receptors, termed 1 and 2. Of these two subtypes, the 1 re- ceptor has been cloned in humans and rodents, and its amino acid sequence shows no homology with other mammalian proteins. Several psychoactive drugs show high to moderate affinity for 1 receptors, including the antipsychotic haloperi- dol, the antidepressant drugs fluvoxamine and sertraline, and the psychostimulants cocaine and methamphetamine; in ad- dition, the anticonvulsant drug phenytoin allosterically modulates 1 receptors. Certain neurosteroids are known to interact with 1 receptors, and have been proposed to be their endogenous ligands. These receptors are located in the plasma membrane and in subcellular membranes, particularly in the endoplasmic reticulum, where they play a modulatory role in 2+ intracellular Ca signaling. Sigma1 receptors also play a modulatory role in the activity of some ion channels and in sev- eral neurotransmitter systems, mainly in glutamatergic neurotransmission. In accordance with their widespread modula- tory role, 1 receptor ligands have been proposed to be useful in several therapeutic fields such as amnesic and cognitive deficits, depression and anxiety, schizophrenia, analgesia, and against some effects of drugs of abuse (such as cocaine and methamphetamine). In this review we provide an overview of the present knowledge of 1 receptors, focussing on 1 ligand neuropharmacology and the role of 1 receptors in behavioral animal studies, which have contributed greatly to the potential therapeutic applications of 1 ligands. Key Words: Sigma-1 receptors, learning and memory, depression and anxiety, schizophrenia, analgesia, pain, drugs of abuse, cocaine. 1. HISTORICAL OVERVIEW: DISCOVERY OF tolabeling studies [65, 159]. In spite of intensive efforts in SIGMA RECEPTORS AND SIGMA RECEPTOR SUB- research on the 2 subtype in recent years [partially reviewed TYPES in 14; 142, 156, 114], the 1 subtype is much better charac- terized, and is the focus of this review. Sigma () receptors were first described as a subclass of opioid receptors [102] to account for the psychotomimetic Sigma1 receptors have been thoroughly studied in an at- actions of (±)-SKF-10,047 (N-allylnormetazocine) and other tempt to elucidate their possible neuropharmacological ap- racemic benzomorphans. This early confusion was due to the plications, mainly in learning and memory processes, depres- complex pharmacology of this racemic compound; later sion and anxiety, schizophrenia, analgesia and some effects studies showed that (–)-SKF-10,047 binds to and opioids, of certain drugs of abuse. In this review we describe some whereas the (+)-isomer lacks affinity for opioid receptors but aspects of the general biology of 1 receptors, but focus on binds to PCP (phencyclidine) binding sites with low affinity, 1 ligand neuropharmacology and the role of 1 receptors in and to a different site with high affinity, which currently behavioral animal studies, which have contributed greatly to retains the designation of [reviewed in 112 and 214 the understanding of the possible neuropharmacological amongst others]. properties of 1 receptors. Non-neuropharmacological effects of ligands such as cardiovascular effects or their effects on Two different sites were distinguished based on their 1 cancer and immunity, and their antitussive effects, are not different drug selectivity pattern and molecular mass; these covered in this review. Therefore this review will not go into two sites are now known as 1 and 2 receptors [64]. It was detail on some aspects of 1 receptor knowledge, and not all reported that 1 binding sites display stereospecificity to- references will be cited. wards dextrorotatory isomers of benzomorphans, whereas 2 binding sites display reverse selectivity, i.e., levorotatory 2. MOLECULAR CHARACTERISTICS, DISTRIBU- isomers display higher affinity than dextrorotatory isomers TION AND PHARMACOLOGICAL PROFILE OF of ligands [e.g. 64, 165]. The molecular weight was found SIGMA1 RECEPTORS to differ between the two receptors subtypes: the recep- 1 2.1. Cloning and Structure of Receptors tor is a 29-kDa single polypeptide first cloned in 1996 [55], 1 whereas 2 receptors have not yet been cloned and have an Significant progress in our knowledge of receptors was apparent molecular weight of 18-21.5 kDa according to pho- made when the 1 receptor was cloned. The 1 receptor is a 29-kDa single polypeptide which was first cloned in guinea- pig liver [55], and later in mouse kidney, a JAR human *Address correspondence to this author at Department of Pharmacology, Faculty of Medicine, Avenida de Madrid 11, University of Granada, 18012 choriocarcinoma cell line, and in the rat and mouse brain Granada, Spain; Tel: +34-958-24-35-38; Fax: +34-958-24-35-37; [reviewed in 54]. The protein is composed by 223 amino E-mail: [email protected] acids and shows the typical 1 binding profile [55, 84, 180]. 1570-159X/08 $55.00+.00 ©2008 Bentham Science Publishers Ltd. Pharmacology and Therapeutic Potential Current Neuropharmacology, 2008, Vol. 6, No. 4 345 The amino acid sequence of the 1 receptor cloned from the these studies high to moderate levels of 1 receptors were human cell line is highly homologous to the 1 receptor associated with the hippocampus, especially in the dentate cloned from the other species [181], and shows no homology gyrus, hypothalamus, olfactory bulb, several cortical layers, with other mammalian proteins, but shares approximately pons, the septum, the central gray, locus ceruleus, dorsal 30% identity with the yeast gene that encodes the C7–C8 raphe, the substantia nigra pars compacta, the red nucleus sterol isomerase [141], and contains an endoplasmic reticu- and various motor cranial nerve nuclei. The cerebellum is lum retention signal at the NH2 terminus [55, 179]. Cloning not particularly enriched in 1 receptors, although some of its of the 1 receptor has contributed greatly to research in this areas, such as the Purkinje cell layer, have been reported to field, making it possible to design specific antisense oligode- show considerable densities of 1 receptors. In addition to oxynucleotides to study 1 receptor function (as will be de- the brain, 1 receptors are also numerous in the spinal cord, scribed below) and develop 1-receptor knockout mice [91]. mainly in the superficial layers of the dorsal horn [2]. Several structures have been proposed for 1 receptors. 2.2.2. Subcellular Distribution of 1 Receptors Initial studies proposed a single transmembrane domain The subcellular distribution of 1 receptors was firstly structure [43, 55]. More recently, Aydar and coworkers pre- studied with radioligand binding in subcellular fractions, and sented evidence that the 1 receptor in the plasma membrane more recently with immunochemical methods. Binding ex- has two transmembrane segments (when expressed in 3 periments with the 1 radioligands [ H](+)-SKF-10,047, Xenopus laevis oocytes) with the NH2 and COOH termini on 3 3 [ H](+)-3-PPP and [ H](+)-pentazocine showed that 1 re- the cytoplasmic side of the membrane [3]. Recent studies ceptors are located in several types of mouse, rat and guinea proposed that in addition to the hydrophobic regions that pig brain membrane. These binding sites are more abundant constitute the putative transmembrane domains, there are in microsomal membranes, which is consistent with the en- two additional hydrophobic segments (one of them partially doplasmic reticulum retention signal of the cloned 1 recep- overlapping the second transmembrane domain), which were tor [55, 179], but they are also present in nuclear, mitochon- proposed to be steroid binding domain-like sites [27], and drial and synaptic membranes [17, 34, 38, 74]. Immunohis- suggesting the existence of two different domains for ligand tochemical studies further confirmed the existence of 1 re- binding in the 1 receptor [159], as previously proposed in ceptors in the endoplasmic reticulum not only in neurons [2], earlier experiments [12]. This proposed model is illustrated but also in many other cell types such as oligodendrocytes in Fig. (1). The pharmacological characterization of these [160], lymphocytes [43], retinal cells [76] and certain cancer putative domains merits further study. cells [62]. Detailed studies by Hayashi and Su in NG108 cells showed that 1 receptors are located as highly clustered 2.2. Anatomical and Subcellular Distribution of 1 Recep- tors globular structures enriched in cholesterol and neutral lipids in the nuclear envelope and endoplasmic reticulum [re- 2.2.1. Anatomical Distribution of 1 Receptors viewed in 62]. In neurons from the rat hypothalamus and hippocampus, electron microscopy studies showed that At the anatomical level receptors are widely distrib- 1 1 receptor immunostaining was mostly associated with neu- uted in peripheral organs [e.g. 192] and different areas of the ronal perikarya, the membrane of mitochondria, some cister-