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Identification of Antagonists Selective for Sigma Receptor Subtypes that are Active In vivo | OMICS International
ISSN: 2329-6488
Journal of Alcoholism & Drug Dependence
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Identification of Antagonists Selective for Sigma Receptor Subtypes that are Active In vivo

Takato Hiranita*

Division of Neurotoxicology, National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), USA

*Corresponding Author:
Takato Hiranita
Division of Neurotoxicology
National Center for Toxicological Research (NCTR)
U.S. Food and Drug Administration (FDA),
3900 NCTR Road, Jefferson, AR 72079-9501, USA
E-mail: [email protected]

Received date: July 07, 2016; Accepted date: July 08, 2016; Published date: July 11, 2016

Citation: Hiranita T (2016) Identification of Antagonists Selective for Sigma Receptor Subtypes that are Active in vivo. J Alcohol Drug Depend 4:e131. doi:10.4172/2329-6488.1000e131

Copyright: © 2016 Hiranita T. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Two antagonists that are active in vivo and selective for the sigma receptor (σR) subtypes, σ1 and σ2, have very recently been described [1]. It is anticipated that these antagonists will contribute to the development of σR pharmacology and medication discovery for stimulant abuse [1].

σRs have been mischaracterized [2-4] and were initially thought to be opioid receptor subtypes [5]. They have been classified into two subtypes based on specific radioligand binding assays using [3H](+)- pentazocine for σ1Rs and [3H]1,3-di-o -tolylguanidine ([3H]DTG), in the presence of (+)-pentazocine to mask the σ1R, for σ2Rs [6-11] (Table 1). The σ1R has already been cloned and is a 25-29 kDa intracellular chaperone protein composed of 223 amino acids [12-14]. In contrast, the [3H](+)-pentazocine-inaccessible σR, the σ2R, is an 18–21 kDa protein that has not yet been cloned. Until recently, there have been no reports of antagonists that are selective for either receptor subtype or that are active in vivo , probably because of the lack of reliable in vivo assays for σR subtypes. The paper by Katz et al. [1] finally identifies antagonists selective for σR subtypes [1] that are active in vivo .

Compound σ1R ([3H](+)-pentazocine) σ2R ([3H]DTG in the presence of (+)-pentazocine) σ21
CM 304 [1] 0.684 (0.552-0.847) 388 (215-702) 567
CM 398 [1] 1,490 (1,200-1,860) 4.50 (2.78-7.27) 0.00302
DTG [11] 57.4 (49.3-66.7) 21.9* (14.8-32.4) 0.382
(+)-Pentazocine [9] 4.59* (4.26-4.97) 224 (195-257) 48.8
PRE-084 [11] 53.2 (44.8-63.2) 32,100 (23,100-44,700) 603

Table 1: Affinities of various compounds for binding to σ1 or σ2 receptors, as well as subtype selectivity (ratio of σ21 binding). The values listed are Ki values (nM) with 95% confidence limits in parentheses.

In this report [1] that utilized radioligand binding and drug selfadministration procedures, σR ligands that were self-administered by cocaine-experienced subjects were classified as σR agonists whereas compounds that failed to maintain self-administration responding above vehicle levels in cocaine-experienced subjects and blocked the self-administration of σR agonists were classified as antagonists. Radioligand binding assays demonstrated that 3-(2-(azepan-1- yl)ethyl)-6-(3-fluoropropyl)benzo[d ]thiazol-2(3H)-one hydrochloride (CM 304) is 567-fold more selective for σ1 than for σ2 receptors (Table 1). In contrast, 1-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)- yl)butyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one hydrochloride (CM 398) is 331-fold more selective for σ2 than σ1 receptors (Table 1).

Behavioral studies in rats trained to self-administer cocaine (0.32-1.0 mg/kg/injection, i.v.) were used to assess whether these two ligands could antagonize self-administration of σR agonists [1].

For example, pretreatment with the selective σ1R ligand CM 304 (0.32-3.2 mg/kg, i.p.) dose-dependently decreased the maximal rate of self-administration responding and the highest dose of CM 304 flattened the inverted U-shaped dose-effect curves for selfadministration of the selective σ1R agonist 2-(4-morpholinethyl)1- phenylcyclohexanecarboxylate hydrochloride (PRE-084, 0.032-1.0 mg/kg/injection, i.v.). In addition, the same range of CM 304 doses also produced dose-dependent insurmountable antagonism of the selfadministration of the σ1R agonist (+)-pentazocine (0.032-1.0 mg/kg/ injection, i.v.) as well as the non-selective σ1/2R agonist DTG (0.1-3.2 mg/kg/injection, i.v.). In contrast, pre-treatment with the selective σ2R ligand CM 398 (up to 3.2 mg/kg, i.p.) was without effects on selfadministration of PRE-084 or (+)-pentazocine. However, CM 304 (0.1-1.0 mg/kg, i.p.) dose-dependently produced insurmountable antagonism of DTG self-administration. Thus, the σ1R-selective CM 304 blocked self-administration of all three σR agonists. However, selfadministration of the non-selective σ1/2R agonist DTG only was sensitive to the σ2R-selective CM 398.

In summary, antagonists selective for σR subtypes have been identified. These antagonists will be useful as experimental tools for studies of σR pharmacology. For example, using CM 304 as a selective σ1R antagonist, it has been demonstrated that σ1Rs are potential treatment targets for stimulant abuse [1]. Further, reports have implicated σ1Rs in various biological functions and drugs acting at these receptors have been studied for their therapeutic effects in cancer, HIV infection, psychiatric disorders, and substance abuse [2-4,15]. Thus, the use of these newly-identified, selective and biologically active ligands will contribute to the understanding of σRrelated disorders.


The present work was supported by the Division of Neurotoxicology/NCTR/U.S. FDA. The information in the present article is not a formal dissemination of information by the FDA and does not represent agency position or policy. The author thanks Dr. Merle G. Paule for comments on the preparation of the manuscript.


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