Sigma 2 Receptor

Sigma-2 receptor (σ₂R), identified as TMEM97, is an endoplasmic-reticulum transmembrane protein linked to cancer biology, NPC1 interaction, and sterol-related regulation^[1]. Mechanistically, TMEM97 cooperates with PGRMC1 and LDLR to form a ternary complex that increases LDL internalization, placing σ₂R research in cholesterol trafficking and membrane-transport studies^[2]. In Alzheimer-related models, the TMEM97-PGRMC1-LDLR complex mediates cellular uptake of Aβ42 and its aggregates, supporting its use in amyloid-uptake experiments^[3]. In tumor models, σ₂R expression tracks proliferative status in solid tumors, making it useful for proliferation-focused oncology research^[4]. Compared with σ₁R, σ₂R/TMEM97 requires subtype-selective ligand validation, because classical DTG binding can overlap with σ₁R assays^[5]. For experimental design, TMEM97 or PGRMC1 knockout did not change sigma-2 ligand-induced cytotoxic EC₅₀ values in HeLa cells, so cytotoxicity should not be assigned automatically to either protein^[5]. For imaging applications,^{[^18F]}ISO-1 PET uptake has been evaluated as a marker of breast-cancer proliferation, linking σ₂R ligands to translational tumor-imaging studies^[6]. Recent cellular studies further show that sigma-2 receptor ligand binding modulates the association between TSPO and TMEM97, expanding mechanistic assays beyond PGRMC1-centered models^[7].

References:

[1]. Alon A, et al. Identification of the gene that codes for the σ₂ receptor. Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):7160-7165. [Content Brief]

[2]. Riad A, et al. Sigma-2 Receptor/TMEM97 and PGRMC-1 Increase the Rate of Internalization of LDL by LDL Receptor through the Formation of a Ternary Complex. Sci Rep. 2018 Nov 15;8(1):16845. [Content Brief]

[3]. Riad A, et al. The Sigma-2 Receptor/TMEM97, PGRMC1, and LDL Receptor Complex Are Responsible for the Cellular Uptake of Aβ42 and Its Protein Aggregates. Mol Neurobiol. 2020 Sep;57(9):3803-3813. [Content Brief]

[4]. Wheeler KT, et al. Sigma-2 receptors as a biomarker of proliferation in solid tumours. Br J Cancer. 2000 Mar;82(6):1223-32. [Content Brief]

[5]. Zeng C, et al. TMEM97 and PGRMC1 do not mediate sigma-2 ligand-induced cell death. Cell Death Discov. 2019 Jan 28;5:58. [Content Brief]

[6]. McDonald ES, et al. Breast Cancer ¹⁸F-ISO-1 Uptake as a Marker of Proliferation Status. J Nucl Med. 2020 May;61(5):665-670. [Content Brief]

[7]. Thejer BM, et al. Sigma-2 Receptor Ligand Binding Modulates Association between TSPO and TMEM97. Int J Mol Sci. 2023 Mar 28;24(7):6381. [Content Brief]

Sigma 2 Receptor Related Products (32):

By Type:	Pan (18) Selective (7)
By Effects:	Agonists (13) Antagonists (9) Activators (2) Ligands (3)

Cat. No.	Product Name	Effect	Purity

HY-111669

Zervimesine	Antagonist	99.01%
Zervimesine (CT1812) is an orally active and brain penetrant sigma-2 receptor antagonist with a K_i of 8.5 nM. Zervimesine can be used for the research of Alzheimer’s disease.

HY-13510

Cutamesine dihydrochloride	Agonist	98.05%
Cutamesine (SA4503) dihydrochloride is a potent and selective sigma 1 receptor agonist with an IC₅₀ of 17.4 nM in guinea pig brain membranes. Cutamesine dihydrochloride shows >100-fold less affinity for the sigma 2 receptor (IC₅₀ of 1784 nM). Cutamesine dihydrochloride has antidepressant effects.

HY-B1813A

(±)-Vesamicol hydrochloride		99.79%
(±)-Vesamicol hydrochloride ((±)-AH5183 hydrochloride) is a potent vesicular acetylcholine transport inhibitor with a K_i of 2 nM. (±)-Vesamicol hydrochloride also displays high affinity for σ1 and σ2 receptors with K_is of 26 nM and 34 nM, respectively.

HY-B2087

Glycerol phenylbutyrate		99.81%
Glycerol phenylbutyrate is a sigma-2 (σ2) receptor ligand, with a pK_i of 8.02. Glycerol phenylbutyrate (GPB) is a new generation ammonia scavenger agent.

HY-14813

Cutamesine	Agonist	99.18%
Cutamesine (SA4503) is a potent and selective sigma 1 receptor agonist with an IC₅₀ of 17.4 nM in guinea pig brain membranes. Cutamesine shows >100-fold less affinity for the sigma 2 receptor (IC₅₀ of 1784 nM). Cutamesine has antidepressant effects.

HY-181007

NMDA receptor antagonist 9
NMDA receptor antagonist 9 is a selective GluN2B subunit-containing NMDA receptor antagonist with a K_i of 5.2 nM. NMDA receptor antagonist 9 exhibits 9-fold selectivity over σ₁ receptors, shows poor selectivity towards σ₂ receptors. NMDA receptor antagonist 9 inhibits ion flux through GluN2B subunit-containing NMDA receptors. NMDA receptor antagonist 9 can be used for the research of neurological disease, such as alzheimer’s disease and parkinson’s disease.

HY-116968

JVW-1009	Antagonist
JVW-1009 is a Sig2R/PGRMC1 antagonist (Sig1R K_i = 96 nM; Sig2R K_i = 70 nM). JVW-1009 acts as a neuroprotective agent. JVW-1009 can be used in the research of Alzheimer's disease.

HY-145628

CM398	Ligand	99.85%
CM398 is a highly selective, orally active Sigma-2 receptor ligand with a K_i value of 0.43 nM. CM398 ameliorates age-related macular degeneration. CM398 exerts analgesic effects on visceral pain, inflammatory pain and neuropathic pain. CM398 can be used in research related to age-related macular degeneration, neuropathic pain and inflammatory pain.

HY-18099

S1RA	Antagonist	98.96%
S1RA (E-52862) is a highly selective σ1 receptor (σ1R) antagonist with K_is of 17 nM and 23.5 nM for human σ1R and guinea pig σ1R, respectively. S1RA has Moderate antagonistic activity for human 5-HT_2B receptor (K_i= 328 nM). S1RA has antinociceptive effects in neuropathic pain models. S1RA prevents mechanical and cold hypersensitivity in Oxaliplatin (HY-17371)-treated mice.

HY-14218

Ditolylguanidine	Agonist	99.75%
Ditolylguanidine (1,3-Di-o-tolylguanidine) is an agonist of sigma receptor (σ1/σ2 receptor) with K_i values of 69 and 21 nM for σ1 and σ2 receptors, respectively. Ditolylguanidine effectively inhibits the growth of small cell lung cancer cells. Ditolylguanidine can be used for the research of lung cancer.

HY-B1055

Pentoxyverine citrate	Agonist	99.57%
Pentoxyverine (Carbetapentane) citrate is an orally active and blood-brain barrier permeability sigma-1 receptor agonist, with K_is of 41 nM, 894 nM and 75 nM for σ1, σ2 and guinea-pig brain membrane σ1, respectively. Pentoxyverine citrate is a muscarinic antagonist. Pentoxyverine citrate is a potent antitussive, anticonvulsant, and spasmolytic agent. Pentoxyverine citrate can be used for inhibiting bronchial interceptor, weakening of cough reflex, bronchial smooth muscle relaxation and reduction of airway resistance.

HY-134004

Pentoxyverine	Agonist	99.56%
Pentoxyverine (Carbetapentane) is an orally active sigma-1 receptor agonist, with K_is of 41 nM, 894 nM and 75 nM for σ1, σ2 and guinea-pig brain membran σ1, respectively. Pentoxyverine is a muscarinic antagonist. Pentoxyverine is a potent antitussive, anticonvulsant, and spasmolytic agent. Pentoxyverine can be used for inhibiting bronchial interceptor, weakening of cough reflex, bronchial smooth muscle relaxation and reduction of airway resistance.

HY-100155

4-IBP	Agonist	98.90%
4-IBP is a selective σ₁ receptor agonist with high affinity for the σ₁ receptor (K_i =1.7 nM) and moderate affinity for the σ₂ receptor (K_i = 25.2 nM). 4-IBP can make cancer cells more sensitive to the cytotoxic effects of pro-apoptotic and pro-autophagic compounds. 4-IBP significantly reduces the migration ability of a variety of cancer cells. 4-IBP is mainly used in glioblastoma, non-small cell lung cancer and prostate cancer research.

HY-135608

BD-1008	Antagonist	98.41%
BD-1008 is a nonselective σ receptor antagonist with K_is against σ1 receptor and σ2 receptor of 2 nM and 8 nM. The BD-1008 has an extremely low affinity for the D2 receptor (K_i = 1112 nM) and dopamine transporter (DAT) (K_i > 10,000 nM). BD-1008 significantly antagonizes dopamine release in the shell region of the nucleus accumbens via the σ₂ receptor. BD-1008 blocks the self-administration behavior of σ agonists.BD-1008 can be used for the study of addiction therapy that target the σ receptor.

HY-149803

S1R agonist 1	Agonist	≥98.0%
S1R agonist 1 (Compound 6b) is a selective S1R agonist with K_is of 0.93 nM and 72 nM for S1R and S2R, respectively. S1R agonist 1 exhibits neuroprotection against ROS and NMDA-induced neurotoxicity.

HY-100966

BD-1008 dihydrobromide	Antagonist	98.07%
BD-1008 dihydrobromide is a nonselective σ receptor antagonist with K_is against σ1 receptor and σ2 receptor of 2 nM and 8 nM. The BD-1008 dihydrobromide has an extremely low affinity for the D2 receptor (K_i = 1112 nM) and dopamine transporter (DAT) (K_i > 10,000 nM). BD-1008 dihydrobromide significantly antagonizes dopamine release in the shell region of the nucleus accumbens via the σ₂ receptor. BD-1008 dihydrobromide blocks the self-administration behavior of σ agonists.BD-1008 dihydrobromide can be used for the study of addiction therapy that target the σ receptor.

HY-117731

UKH-1114	Agonist	99.88%
UKH-1114 is a selective TMEM97 (a sigma-2 receptor) agonist with a K_i values of 1279 and 46 nM for σ1R and σ2R/TMEM97, respectively. UKH-1114 exhibits exceptional selectivity with negligible affinity for over 50 other receptors and channels. UKH-1114 effectively relieves spared nerve injury (SNI)-induced mechanical hypersensitivity with a long-lasting duration and without motor impairment. UKH-1114 can be used for neuropathic pain research.

HY-149804

S1R agonist 2	Agonist	≥98.0%
S1R agonist 2 (Compound 8b) is a selective S1R agonist with K_is of 1.1 nM and 88 nM for S1R and S2R, respectively. S1R agonist 2 exhibits neuroprotection against ROS and NMDA-induced neurotoxicity.

HY-149855

AB10	Antagonist
AB10 is a selective S1R antagonist. AB10 with K_i of 10, 165 nM for S1R and S2R, respectively. AB10 reverses the effect of Capsaicin (HY-10448) caused pain in model.

HY-174155

Sigma-2 Receptor ligand 1	Ligand
Sigma-2 Receptor ligand 1 (Compound 7i) is a highly selective Sigma-2 receptor ligand with a K_i value of 40 nM. Sigma-2 Receptor ligand 1 is promising for research of Alzheimer's disease.

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