Alpha-7 nicotinic receptor

The alpha-7 nicotinic receptor (α7)₅ is a type of nicotinic acetylcholine receptor, consisting entirely of α7 subunits Pharmacology, (Rang, Dale, Ritter & Moore, ISBN 0443071454, 5:th ed., Churchill Livingstone 2003) Page 138. ] .

It is located in the brain, where activation yields post- and presynaptic excitation, mainly by increased Ca²⁺ permeability.

Ligands

Agonists

*(+)-"N"-(1-azabicyclo [2.2.2] oct-3-yl)benzo ["b"] furan- 2-carboxamide: potent and highly subtype-selective [cite journal |author=Mazurov A, Klucik J, Miao L, "et al" |title=2-(Arylmethyl)-3-substituted quinuclidines as selective alpha 7 nicotinic receptor ligands |journal=Bioorg. Med. Chem. Lett. |volume=15 |issue=8 |pages=2073–7 |year=2005 |pmid=15808471 |doi=10.1016/j.bmcl.2005.02.045 |url=]
*PHA-709829: potent and subtype-selective; robust in vivo efficacy in a rat auditory sensory gating model [cite journal |author=Acker BA, Jacobsen EJ, Rogers BN, "et al" |title=Discovery of N- [(3R,5R)-1-azabicyclo [3.2.1] oct-3-yl] furo [2,3-c] pyridine-5-carboxamide as an agonist of the alpha7 nicotinic acetylcholine receptor: in vitro and in vivo activity |journal=Bioorg. Med. Chem. Lett. |volume=18 |issue=12 |pages=3611–5 |year=2008 |pmid=18490160 |doi=10.1016/j.bmcl.2008.04.070 |url=]
**analogs: improved hERG safety profile over PNU-282,987 [cite journal |author=Walker DP, Wishka DG, Piotrowski DW, "et al" |title=Design, synthesis, structure-activity relationship, and in vivo activity of azabicyclic aryl amides as alpha7 nicotinic acetylcholine receptor agonists |journal=Bioorg. Med. Chem. |volume=14 |issue=24 |pages=8219–48 |year=2006 |pmid=17011782 |doi=10.1016/j.bmc.2006.09.019 |url=]
*A-582941: partial agonist; activates ERK1/2 and CREB phosphorylation; enhances cognitive performance [cite journal |author=Tietje KR, Anderson DJ, Bitner RS, "et al" |title=Preclinical characterization of A-582941: a novel alpha7 neuronal nicotinic receptor agonist with broad spectrum cognition-enhancing properties |journal=CNS Neurosci Ther |volume=14 |issue=1 |pages=65–82 |year=2008 |pmid=18482100 |doi=10.1111/j.1527-3458.2008.00037.x |url=]
*TC-1698: subtype-selective; neuroprotective effects via activation of the JAK2/PI-3K cascade, neutralized by angiotensin II AT(2) receptor activation [cite journal |author=Marrero MB, Papke RL, Bhatti BS, Shaw S, Bencherif M |title=The neuroprotective effect of 2-(3-pyridyl)-1-azabicyclo [3.2.2] nonane (TC-1698), a novel alpha7 ligand, is prevented through angiotensin II activation of a tyrosine phosphatase |journal=J. Pharmacol. Exp. Ther. |volume=309 |issue=1 |pages=16–27 |year=2004 |pmid=14722323 |doi=10.1124/jpet.103.061655 |url=]
* TC-5619 - partial agonist, in development for treatment of schizophrenia
* GTS-21 - partial agonist, in development for treatment of schizophrenia and/or Alzheimer's disease
*SSR180711: partial agonist [cite journal |author=Biton B, Bergis OE, Galli F, "et al" |title=SSR180711, a novel selective alpha7 nicotinic receptor partial agonist: (1) binding and functional profile |journal=Neuropsychopharmacology |volume=32 |issue=1 |pages=1–16 |year=2007 |pmid=17019409 |doi=10.1038/sj.npp.1301189 |url=]
*tropisetron: subtype-selective partial agonist; 5-HT₃ receptor antagonist [cite journal |author=Macor JE, Gurley D, Lanthorn T, "et al" |title=The 5-HT3 antagonist tropisetron (ICS 205-930) is a potent and selective alpha7 nicotinic receptor partial agonist |journal=Bioorg. Med. Chem. Lett. |volume=11 |issue=3 |pages=319–21 |year=2001 |pmid=11212100 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0960894X00006703]

Antagonists

*α-conotoxin ArIB [V11L,V16D] : potent and highly subtype-selective; slowly reversible [cite journal |author=Whiteaker P, Christensen S, Yoshikami D, "et al" |title=Discovery, synthesis, and structure activity of a highly selective alpha7 nicotinic acetylcholine receptor antagonist |journal=Biochemistry |volume=46 |issue=22 |pages=6628–38 |year=2007 |pmid=17497892 |doi=10.1021/bi7004202 |url=]
*quinolizidine (–)-1-epi-207I: α7 subtype preferring blocker [cite journal |author=Tsuneki H, You Y, Toyooka N, "et al" |title=Alkaloids indolizidine 235B', quinolizidine 1-epi-207I, and the tricyclic 205B are potent and selective noncompetitive inhibitors of nicotinic acetylcholine receptors |journal=Mol. Pharmacol. |volume=66 |issue=4 |pages=1061–9 |year=2004 |pmid=15258256 |doi=10.1124/mol.104.000729 |url=]

PAMs

At least two types of positive allosteric modulators (PAMs) can be distinguished. [cite journal |author=Grønlien JH, Håkerud M, Ween H, "et al" |title=Distinct profiles of alpha7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes |journal=Mol. Pharmacol. |volume=72 |issue=3 |pages=715–24 |year=2007 |pmid=17565004 |doi=10.1124/mol.107.035410 |url=]

*PNU-120596 [cite journal |author=Hurst RS, Hajós M, Raggenbass M, "et al" |title=A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization |journal=J. Neurosci. |volume=25 |issue=17 |pages=4396–405 |year=2005 |pmid=15858066 |doi=10.1523/JNEUROSCI.5269-04.2005 |url=]
*NS-1738: marginal effects on α7 desensitization kinetics; modestly brain-penetrant [cite journal |author=Timmermann DB, Grønlien JH, Kohlhaas KL, "et al" |title=An allosteric modulator of the alpha7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo |journal=J. Pharmacol. Exp. Ther. |volume=323 |issue=1 |pages=294–307 |year=2007 |pmid=17625074 |doi=10.1124/jpet.107.120436 |url=]

References