Alpha-7 nicotinic receptor

Molecular model of the α₇ nicotinic receptor.

The alpha-7 nicotinic receptor, also known as the α7 receptor, is a type of nicotinic acetylcholine receptor implicated in long term memory, consisting entirely of α7 subunits.^[1] As with other nicotinic acetylcholine receptors, functional α7 receptors are pentameric [i.e., (α7)₅ stoichiometry].

It is located in the brain, spleen, and lymphocytes of lymph nodes where activation yields post- and presynaptic excitation,^[1] mainly by increased Ca²⁺ permeability.

Medical relevance

Recent work has demonstrated a potential role in reducing inflammatory neurotoxicity in stroke, myocardial infarction, sepsis, and alzheimers disease.^[2][3][4]

An α7 nicotinic agonist appears to have positive effects on neurocognition in persons with schizophrenia.^[5]

Both α4β2 and α7 nicotinic receptors appear to be critical for memory, working memory, learning, and attention.^[6]

α7-nicotinic receptors also appear to be involved in cancer progression. They have been shown to mediate cancer cell proliferation and metastasis.^[7] α7 receptors are also involved in angiogenic activity, and have anti-apoptotic effects.^[8][9]

Ligands

Agonists

• (+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan- 2-carboxamide: potent and highly subtype-selective^[10]
• A-582941: partial agonist; activates ERK1/2 and CREB phosphorylation; enhances cognitive performance^[11]
• AR-R17779: full agonist, nootropic
• Amyloid beta: neurotoxic marker of Alzheimer's disease ^[12]
• TC-1698: subtype-selective; neuroprotective effects via activation of the JAK2/PI-3K cascade, neutralized by angiotensin II AT(2) receptor activation^[13]
• TC-5619 - partial agonist, in development for treatment of schizophrenia
• EVP-6124 - partial agonist with nootropic properties, in development for treatment of schizophrenia and Alzheimer's disease ^[14][15]
• GTS-21 - partial agonist, in development for treatment of schizophrenia and/or Alzheimer's disease
• PHA-543,613 - selective and potent agonist with nootropic properties ^[16]
• PNU-282,987 - selective and potent agonist, but may cause long QT syndrome
• PHA-709829: potent and subtype-selective; robust in vivo efficacy in a rat auditory sensory gating model^[17]
  • Analogues: improved hERG safety profile over PNU-282,987^[18]
• SSR-180,711: partial agonist^[19]
• Tropisetron: subtype-selective partial agonist; 5-HT₃ receptor antagonist^[20]
• WAY-317,538 - selective potent full agonist with nootropic and neuroprotective properties
• Anabasine
• Acetylcholine
• Nicotine
• Choline ^[21]
• ICH-3: subtype-selective partial agonist;^[22]

Positive Allosteric Modulators (PAMs)

At least two types of positive allosteric modulators (PAMs) can be distinguished.^[23]

• PNU-120,596^[24]
• NS-1738: marginal effects on α₇ desensitization kinetics; modestly brain-penetrant^[25]
• AVL-3288: unlike the above PAMs, AVL-3288 does not affect α₇ desensitization kinetics, and is readily brain penetrant. Improves cognitive behavior in animal models^[26] In clinical development for cognitive deficits in schizophrenia.
• A-867744^[27][28]
• Ivermectin
• Galantamine

Other

• Nefiracetam^[29][30][31]

Antagonists

It is found that anandamide and ethanol cause an additive inhibition on the function of α₇-receptor by interacting with distinct regions of the receptor. Although ethanol inhibition of the α₇-receptor is likely to involve the N-terminal region of the receptor, the site of action for anandamide is located in the transmembrane and carboxyl-terminal domains of the receptors.^[32]

• Anandamide
• α-Bungarotoxin
• α-Conotoxin ArIB[V11L,V16D]: potent and highly subtype-selective; slowly reversible^[33]
• Bupropion (very weakly)
• Dehydronorketamine
• Ethanol
• Hydroxybupropion (very weakly)
• Hydroxynorketamine
• Ketamine
• Kynurenic acid
• Memantine
• Lobeline
• Methyllycaconitine ^[16]
• Norketamine
• Quinolizidine (–)-1-epi-207I: α₇ subtype preferring blocker^[34]

See also

• α3β2-Nicotinic receptor
• α3β4-Nicotinic receptor
• α4β2-Nicotinic receptor
• RIC3, a chaperone protein for α7 receptors
• Endocannabinoids

References

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