Sigma Receptors

Although they have undergone a substantial transformation from the time they were first proposed in the mid-1970s, a unifying picture appears to be emerging for sigma receptors. Current interest is related to the possibility that sigma receptors may constitute favorable targets for drug design in conditions such as psychiatric and movement disorders, amnesia, depression, cancer, inflammation and cocaine addiction. To achieve this aim, it is necessary to characterize the binding sites pharmacologically and identify selective ligands.

It is now generally accepted that there are two sigma receptor subtypes, referred to as σƒ-1 and σƒƒ-2. However, despite evidence for the existence of "€œsigma binding substances"€, endogenous ligands have yet to be identified. Current knowledge regarding the molecular nature of the sigma receptors has improved in recent years. For example, using photo-affinity labeling, the σƒ-1 receptor was found to have a molecular weight of 25 kDa, while a value of 18-21 kDa was determined for the σƒƒ-2 receptor. The σƒ-1 receptor has also been cloned from guinea pig, rat, mouse and human tissue and shows a greater than 90% species homology. Although it possesses no enzymatic activity, the σƒ-1 receptor has a sequence similarity to the fungal D8,7-isomerase enzyme. This, and perhaps the fact that steroids have moderate affinity at sigma receptors, has led to suggestions that they may play a role in neurosteroid biosynthesis. However, no homology exists between the σƒ-1 receptor and the mammalian D8,7-isomerase enzyme.

Steroids display moderate to weak binding affinities at sigma receptors. Because there are no known endogenous ligands for the sigma receptors, the focus has remained on steroids behaving as possible endogenous ligands for sigma receptors. Consistent with this idea is the fact that steroids may effect several physiological actions through sigma receptors. Yet there is evidence suggesting that sigma ligands may require a nitrogen atom, possibly in the protonated form, as a pharmacophore element, to achieve high affinity binding at the σƒ-1 receptor. Interestingly, steroids do not contain a nitrogen atom.

The σƒ-1 subtype is characterized by its high affinity and selectivity towards the (+)-stereoisomer of the benzomorphans and is found in high levels in guinea-pig brain. It has been shown to regulate central cholinergic function, negatively modulate agonist-stimulated phosphoinositide turnover, modulate dopamine release from dopaminergic neurons, modulate NMDA-type glutamate receptor electrophysiology, modulate opioid analgesia, inhibit amnesia, provide neuroprotection, and activate pyramidal neurons in the hippocampus of the rat through NMDA induction. Based on the later pharmacological property, several compounds are now classified as either putative receptor agonists, including (+)-pentazocine, L-687,384, BD 737, JO-1784 or putative antagonists, haloperidol, BMY 14802, DuP 734, NE-100, AC915, E5842 and MS-377. [3H]-Pentazocine is the primary selective radioligand for the determination of binding affinities at the σƒ-1 receptor. More recently, it has been confirmed that σƒ-1 selective ligands do attenuate cocaine-induced toxicity in animal models and they might play a role as anti-cocaine agents in man.

The picture is less clear with regard to the σƒ-2 sigma receptor primarily because of the lack of σƒ-2 selective agents. In contrast to σƒ-1 sigma receptors, σƒ-2 receptors show a slight preference for the (–€“)-stereo isomers of the benzomorphans. Apart from the nervous system, high densities are found in liver and kidney and very high densities in tumor cell lines derived from various tissues, including gliomas, neuroblastomas, melanoma and carcinoma cell lines of breast, prostate and lung. Interestingly, σƒ-2 selective agonists have been shown to induce cell death in C6 glioma cell lines from both neuronal and non-neuronal origins. The mode of this cell death has been elucidated to be apoptotic in nature and modulation of intracellular calcium may play a role. Current evidence suggests that while σƒ-2 agonists may be useful as anticancer agents, σ-2 antagonists may find therapeutic utility in attenuating the motor side effects associated with typical antipsychotics. Alternatively, antipsychotic agents without sigma-binding affinity may serve as novel antipsychotics without the acute and long-term extrapyramidal side effects associated with current drugs.

DTG is a non-selective ligand for σ-1 and σ-2 receptors, but [3H]-DTG (in the presence of dextrallorphan to mask σ-1 sites) serves as an effective radioligand for determining binding affinity at σ-2 receptors. While these receptors have been implicated in cell proliferation and motor disturbances, the lack of selective ligands has hampered their full pharmacological characterization. Currently identified selective σ-2 ligands include CB 184, BIMU-8, CB 64D, ibogaine, ifenprodil, SM-21and Lu28-179.


The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.


Currently Accepted Name σ-1 σ-2
Alternate Name Sigma-1 Sigma-2
Ligands (+)-Pentazocine (P127)a
Rigmarole (346438)a
L-687,384 (L8539)a
BD 737a
DTG (207713)
(+)SKF-10,047 (A114)
Haloperidol (H1512)b
BMY 14802b
R(+)-3-PPP (P102)b
DuP 734b
NE-100 (SML0631)b
DTG (207713)
Ifenprodil (I2892)
CB 184
CB 64D
Signal Transduction Mechanisms Not Known
Not Known
Radioligands of Choice [3H]-(+)-Pentazocine [3H]-DTG
Tissue Expression Brain, heart Liver, brain
Physiological Function Poorly characterized Poorly characterized
Disease Relevance Neuropsychitric disorders, depression, amnesia, anti-cocaine Cancer, motor disorders



a) Putative σ receptor agonists.

b) Putative σ receptor antagonists.



AC915: 2-(1-Pyrrolidinyl)ethyl 3,4-dichlorophenylacetate oxalate
BD 737: 1S,2R-(+)-cis-N-[2-(3,4-Dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)cyclohexyl amine
BIMU-8: Endo-N-(8-Methyl-8-azabicyclo[3,2,1]oct-3-yl)-2,3-dihydro-(1-methyl)ethyl-2-oxo-1H-benzimidazole-1-carboxamide HCl
BMY 14802: a-(4-Fluorophenyl)-4-(5-fluoro-2-pyridinyl)-1-piperazinebutanol
CB 184: (+)-1R,5R-(E)-8-(3,4-Dichlorobenzylidine-5-(3-hydroxyphenyl)-2-methylmorpharn-7-one
CB 64D: (+)-1R,5R-B)-8-Benzylidine-5-(3-hydroxyphenyl)-2-methylmorpharn-7-one
DTG: Di(2-tolyl)guanidine
DuP 734: 1-(Cyclopropylmethyl)-4-[2-(4′′-fluorophenyl)oxoethyl]piperidine HBr
E5842: 4-[4-Fluorophenyl]-1,2,3,6-tetrahydro-1-[4-{1,2,4-triazol-1-yl}butyl]pyridine citrate
JO-1784: (+)-N-Cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethylbut-3-en-1-ylamine
L-687,384: 1-Benzylspiro(1,2,3,4-tetrahydronaphthalene-1,4-piperidine)
Lu28-179: 1′-[4-[1-(4-Fluorophenyl)-1-H-indol-3-yl]-1-butyl]spiro[iso-benzofuran-1(3H),4′-piperidine]
MS-377: (R)-(+)-1-(4-Chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate
NE-100: N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine
3-PPP: 3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine
SA4503: 1-(3,4-Dimethoxyphenethyl)-4-(phenylpropyl)piperazine
(+)-SKF-10,047: (+)-N-Allylnormetazocine hydrochloride
SM-21: 3-α-Tropanyl-2-(4-chlorophenoxy)butyrate


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