NMDA receptor antagonist | BIII 277CL
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Highlights
BIII 277CL is a high affinity blocker of the NMDA receptor ion channel with specificity over other binding sites of the NMDA receptor–channel complex. In addition, BIII 277CL did not exhibit significant affinities for other central neurotransmitter receptors.
BIII 277CL also antagonized NMDA-induced [3H]noradrenaline release and NMDA-induced inhibition of protein synthesis in rat hippocampal slices.
In mice, the molecule prevented NMDA-induced lethality and caused disturbances in motor coordination. Furthermore, intraperitoneal or subcutaneous application of BIII 277CL to mice dose-dependently reduced the cortical infarct area from focal cerebral ischemia by unilateral occlusion of the middle cerebral artery.
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Target information
The NMDA receptor is a subtype of excitatory amino acid receptor found in nerve cells, which allows cationic influx upon activation by glutamate and glycine.
Structurally, the NMDA receptor–channel complex consists of a voltage-dependent Na+/Ca2+ channel and at least 3 different regulatory domains: neurotransmitter recognition site (glutamate, aspartate, or NMDA binding site), strychnine-insensitive glycine site, and ion channel itself (can be blocked by Mg2+ or other blockers).
During ischemia, large amounts of glutamate and aspartate (excitatory neurotransmitters) are released into the extracellular space, which can lead to neuronal deaths. This implicates the NMDA receptor–channel complex with pathophysiology of numerous neurological disorders, such as stroke, epilepsy, Alzheimer’s disease, ALS, and others.
Structure of the NMDA receptor from Xenopus laevis (4TLM.pdb; Lee et. al., Nature 511 (2014), p.191-197)
In vitro Activity
BIII 277CL is a high affinity blocker of the NMDA receptor ion channel (Ki = 4.5 nM; [3H]MK-801 displacement assay in rat brain synaptosomal membrane) with specificity over other binding sites of the NMDA receptor–channel complex (glycine and NMDA binding sites). In addition, BIII 277CL did not exhibit significant affinities for other central neurotransmitter receptors.
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PROBE NAME / NEGATIVE CONTROL |
BIII 277CL |
BI-25CL |
|
MW [Da] |
339.1 (HCl Salt) |
339.1 (HCl Salt) |
|
Displacement of [3H]MK-801 Ki [nM]a MK-801: dizocilpine |
4.5 |
>50,000 |
a Assay conditions see reference 1
In vitro DMPK and CMC parameters
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PROBE NAME / NEGATIVE CONTROL |
BIII 277CL |
BI-25CL |
|
Solubility @ pH 7 [µg/ml] |
>38 |
>74 |
|
Solubility @ pH 4 [µg/ml] |
53.7 |
>77 |
|
CACO permeability @ pH 7.4 [*10-6 cm/s] |
ongoing |
ongoing |
|
CACO efflux ratio |
ongoing |
ongoing |
|
MDCK permeability Pappa-b/b-a @ 1µM [10-6 cm/s] |
ongoing |
ongoing |
|
MDCK efflux ratio |
ongoing |
ongoing |
|
Microsomal stability (human) [% QH] |
49 |
ongoing |
|
Hepatocyte stability (human/mouse/rat) [% QH] |
ongoing |
ongoing |
|
Plasma protein binding (human/mouse/rat) [%] |
ongoing |
ongoing |
|
CYP 3A4 (IC50) [µM] |
>50 |
>50 |
|
CYP 2C8 (IC50) [µM] |
>50 |
>50 |
|
CYP 2C9 (IC50) [µM] |
>50 |
>50 |
|
CYP 2C19 (IC50) [µM] |
>50 |
18.5 |
|
CYP 2D6 (IC50) [µM] |
14.7 |
>50 |
In vivo DMPK parameters
|
BIII 277CL |
RAT |
|
Clearance [% QH]b |
ongoing |
|
tmax [h] |
0.3 |
|
Cmax [nM]a |
2.691 |
|
F [%] |
4.301 |
|
Vss [l/kg] |
>100.000 |
b dose [mg/kg]
In vivo pharmacology
In mice, BIII 277CL showed significant neuroprotective effects. The molecule prevented NMDA-induced lethality and caused disturbances in motor coordination (ID50 = 0.54 mg/kg s.c. and ED50 = 0.47 mg/kg s.c., respectively).
Furthermore, intraperitoneal or subcutaneous application of BIII 277CL to mice dose-dependently reduced the cortical infarct area from focal cerebral ischemia by unilateral occlusion of the middle cerebral artery.
Negative control
In addition, we offer a structurally closely related BI-25CL, which showed no marked affinity at the NMDA receptor ion channel (Ki = 50 mM; [3H] MK-801 displacement assay in rat brain synaptosomal membrane) to be used as a control compound in in vitro studies.
BI-25CL which serves as a negative control
Selectivity
BIII 277CL displayed only weak affinities for σ- and m-opiate binding sites ([3H]DTG, [3H]dihydromorphine [3H]naloxone displacement assays in rat brain synaptosomal membrane) and 200-fold selectivity toward the channel site of the NMDA receptor–channel complex with no marked affinities up to 10 mM for the glycine site and the NMDA binding site of the NMDA receptor–channel complex.
Additionally, BIII 277CL did not exhibit affinities up to 100 mM for the dopamine D1 and D2 receptors ([3H]SCH 23390 and [3H]spiroperidol displacement assay).
|
BIII 277CL |
SELECTIVITY DATA AVILABLE |
|
Cerep® |
Ongoing |
|
Panlabs® |
No |
|
Invitrogen® |
No |
|
DiscoverX® |
No |
|
Dundee |
No |
reference molecules
For an overview of NMDA receptor antagonists please refer to the corresponding Wikipedia article and references therein.
Summary
BIII 277CL is a selective high affinity blocker of the NMDA receptor ion channel (Ki = 4.5 nM), which displayed beneficial effects in reducing the cortical infarct area in mice with focal cerebral ischemia.
We offer BIII 277CL to test biological hypotheses in vitro and in vivo.
Supplementary data
References
Synthesis and structure-activity relationships of 6,7-benzomorphan derivatives as use-dependent sodium channel blockers for the treatment of stroke
Matthias Grauert, Wolf. D. Bechtel, Thomas Weiser, Werner Stransky, Herbert Nar, Adrian J. Carter
J. Med. Chem. 1997, 40, 2922-2930.
BIII 277 CL Is a Potent and Specific Ion-channel Blocker of the NMDA Receptor−Channel Complex
Adrian J. Carter, Wolf D. Bechtel, Matthias Grauert, Paul Harrison, Herbert Merz and Werner Stransky
J. Pharmacol. Exp. Ther. 1995, 275, 1382-1389.
N-Methyl-D-Aspartate Receptor Channel Block by the Enantiomeric 6,7-Benzomorphans BIII 277 CL and BIII 281 CL
Matthias Grauert, Jong M. Rho, Swaminathan Subramaniam, and Michael A. Rogawski
J. Pharmacol. Exp. Ther. 1998, 285, 767-776.
The Influence of Repeated Doses, Route and Time of Administration on the Neuroprotective Effects of BIII 277 CL in a Rat Model of Focal Cerebral Ischemia
Uwe Pschorn and Adrian J. Carter
J. Stroke Cerebrovasc. Dis. 1996, 6, 93-99.
The importance of voltage-dependent sodium channels in cerebral ischaemia
Adrian J. Carter
Amino Acids 1998, 14, 159-169.
