A 844606 - CAS 861119-08-6
Category: Inhibitor
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Molecular Formula:
Molecular Weight:
A 844606 is a selective α7 nicotinic acetylcholine receptor (nAChR) partial agonist (EC50 = 1.4 and 2.2 μM at human and rat receptors, respectively). It has no measurable effect on α4β2 nAChRs.
Brife Description:
α7 nAChR partial agonist
≥99% by HPLC
Canonical SMILES:
1.Characterization of [(3)H]CHIBA-1001 binding to alpha7 nicotinic acetylcholine receptors in the brain from rat, monkey, and human.
Tanibuchi Y;Wu J;Toyohara J;Fujita Y;Iyo M;Hashimoto K Brain Res. 2010 Aug 12;1348:200-8. doi: 10.1016/j.brainres.2010.06.008. Epub 2010 Jun 9.
Accumulating evidence suggests that the alpha7 subtype of nicotinic acetylcholine receptors (nAChRs) plays a role in the pathophysiology of neuropsychiatric diseases, including schizophrenia and Alzheimer's disease. Currently, there are no suitable small molecule radioligands for alpha7 nAChRs in the brain, although [(125)I]alpha-bungarotoxin has been widely used as a radioligand for alpha7 nAChRs. In the present study, we characterized a new radioligand, 4-[(3)H]methylphenyl 2,5-diazabicyclo[3.2.2]nonane-2-carboxylate ([(3)H]CHIBA-1001), a derivative of the selective alpha7 nAChR agonist SSR180711, in brain membranes from rat, monkey, and human. Scatchard analysis revealed an apparent equilibrium dissociation constant (Kd) of 193.4nM in rat brain membranes at 4 degrees C, and the maximal number of binding sites (Bmax) was 346.2fmol/mg protein. The order of drugs for the inhibition of [(3)H]CHIBA-1001 binding to rat brain membranes is SSR180711>A-844606>MG624>epibatidine>DMAB>A-582941, suggesting a similarity of alpha7 nAChR pharmacological profiles. In contrast, alpha-bungarotoxin, MLA, and nicotine were found to be very weak. The distribution of [(3)H]CHIBA-1001 binding to crude membranes from dissected regions of rat, monkey, and human brain was different from that of [(125)I]alpha-bungarotoxin binding, suggesting that [(3)H]CHIBA-1001 binding sites may not be identical to [(125)I]alpha-bungarotoxin binding in the brain.
2.alpha7 nicotinic acetylcholine receptor agonist properties of tilorone and related tricyclic analogues.
Briggs CA;Schrimpf MR;Anderson DJ;Gubbins EJ;Grønlien JH;Håkerud M;Ween H;Thorin-Hagene K;Malysz J;Li J;Bunnelle WH;Gopalakrishnan M;Meyer MD Br J Pharmacol. 2008 Mar;153(5):1054-61. Epub 2007 Dec 24.
BACKGROUND AND PURPOSE: ;The alpha7 nicotinic acetylcholine receptor (nAChR) has attracted considerable interest as a target for cognitive enhancement in schizophrenia and Alzheimer's Disease. However, most recently described alpha7 agonists are derived from the quinuclidine structural class. Alternatively, the present study identifies tilorone as a novel alpha7-selective agonist and characterizes analogues developed from this lead.;EXPERIMENTAL APPROACH: ;Activity and selectivity were determined from rat brain alpha7 and alpha4beta2 nAChR binding, recombinant nAChR activation, and native alpha7 nAChR mediated stimulation of ERK1/2 phosphorylation in PC12 cells.;KEY RESULTS: ;Tilorone bound alpha7 nAChR (IC(50) 110 nM) with high selectivity relative to alpha4beta2 (IC(50) 70 000 nM), activated human alpha7 nAChR with an EC(50) value of 2.5 microM and maximal response of 67% relative to acetylcholine, and showed little agonist effect at human alpha3beta4 or alpha4beta2 nAChRs. However, the rat alpha7 nAChR maximal response was only 34%. Lead optimization led to 2-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-xanthen-9-one (A-844606) with improved binding (alpha7 IC(50) 11 nM, alpha4beta2 IC(50)>30 000 nM) and activity at both human and rat alpha7 nAChR (EC(50)s 1.
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CAS 861119-08-6 A 844606

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