AM-36 - CAS 199467-52-2
Catalog number: 199467-52-2
Category: Inhibitor
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Molecular Formula:
C27H39ClN2O2
Molecular Weight:
459.06
COA:
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Targets:
NMDA Receptor | Sodium Channel
Description:
AM-36 is a potent blocker of batrachotoxinin (BTX)-sensitive Na+ channel binding in rat brain homogenates with an IC50 of 0.28 microM. As a unique neuroprotective agent with anti-oxidant activity, in neuronal cell cultures, AM-36 inhibited toxicity induced by N-methyl-D-aspartate (NMDA) and the sodium channel opener veratridine and, in addition, inhibited veratridine-induced apoptosis.
Purity:
>98%
Appearance:
Solid powder
Synonyms:
2,6-ditert-butyl-4-[[4-[2-(4-chlorophenyl)-2-hydroxyethyl]piperazin-1-yl]methyl]phenol; AM-36; AM 36; AM36; UNII-08OBY024NY; SCHEMBL12311270; CNSB 002; CNSB-002; CNSB002
MSDS:
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InChIKey:
ZGSFWANJADAZQC-UHFFFAOYSA-N
InChI:
1S/C27H39ClN2O2/c1-26(2,3)22-15-19(16-23(25(22)32)27(4,5)6)17-29-11-13-30(14-12-29)18-24(31)20-7-9-21(28)10-8-20/h7-10,15-16,24,31-32H,11-14,17-18H2,1-6H3
Canonical SMILES:
CC(C)(C)C1=CC(=CC(=C1O)C(C)(C)C)CN2CCN(CC2)CC(C3=CC=C(C=C3)Cl)O
1.Incorporation of sodium channel blocking and free radical scavenging activities into a single drug, AM-36, results in profound inhibition of neuronal apoptosis.
Callaway JK;Beart PM;Jarrott B;Giardina SF Br J Pharmacol. 2001 Apr;132(8):1691-8.
AM-36 is a novel neuroprotective agent incorporating both antioxidant and Na(+) channel blocking actions. In cerebral ischaemia, loss of cellular ion homeostasis due to Na(+) channel activation, together with increased reactive oxygen species (ROS) production, are thought to contribute to neuronal death. Since neuronal death in the penumbra of the ischaemic lesion is suggested to occur by apoptosis, we investigated the ability of AM-36, antioxidants and Na(+) channel antagonists to inhibit toxicity induced by the neurotoxin, veratridine in cultured cerebellar granule cells (CGC's). Veratridine (10 - 300 microM) concentration-dependently reduced cell viability of cultured CGC's. Under the experimental conditions employed, cell death induced by veratridine (100 microM) possessed the characteristics of apoptosis as assessed by morphology, TUNEL staining and DNA laddering on agarose gels. Neurotoxicity and apoptosis induced by veratridine (100 microM) were inhibited to a maximum of 50% by the antioxidants, U74500A (0.1 - 10 microM) and U83836E (0.03 - 10 microM), and to a maximum of 30% by the Na(+) channel blocker, dibucaine (0.1 - 100 microM). In contrast, AM-36 (0.01 - 10 microM) completely inhibited veratridine-induced toxicity ( IC(50) 1.
2.Delayed treatment with AM-36, a novel neuroprotective agent, reduces neuronal damage after endothelin-1-induced middle cerebral artery occlusion in conscious rats.
Callaway JK;Knight MJ;Watkins DJ;Beart PM;Jarrott B Stroke. 1999 Dec;30(12):2704-12; discussion 2712.
BACKGROUND AND PURPOSE: ;AM-36 is a novel arylalkylpiperazine with combined antioxidant and Na(+) channel blocking actions. Individually, these properties have been shown to confer neuroprotection in a variety of in vitro and in vivo animal models of stroke. Preliminary studies have shown that AM-36 is neuroprotective in vivo. The purpose of the present study was to assess the neuroprotective and behavioral outcome after delayed administration of AM-36 in an endothelin-1-induced, middle cerebral artery model of cerebral ischemia in conscious rats.;METHODS: ;Conscious male hooded Wistar rats were subjected to middle cerebral artery occlusion by perivascular microinjection of endothelin-1 via a previously implanted cannula. AM-36 (6 mg/kg IP) or vehicle was administered intraperitoneally 30, 60, or 180 minutes after middle cerebral artery occlusion. Functional outcome was determined 24, 48, and 72 hours after stroke by neurological deficit score, motor performance, and sensory hemineglect tests. Rats were killed at 72 hours, and infarct area and volume were determined by histology and computerized image analysis.;RESULTS: ;Endothelin-1-induced middle cerebral artery occlusion resulted in marked functional deficits and neuronal damage.
3.Investigation of AM-36: a novel neuroprotective agent.
Callaway JK Clin Exp Pharmacol Physiol. 2001 Nov;28(11):913-8.
1. The neurochemical sequelae following cerebral ischaemia are complex, involving excess release of excitatory amino acids, particularly glutamate, disruption of ionic homeostasis due to Na+ and Ca2+ influx and generation of toxic free radicals, ultimately leading to cell death by both necrosis and apoptosis. 2. Drugs that block components of this biochemical cascade, such as glutamate receptor antagonists, sodium channel blockers and free radical scavengers, have been investigated as putative neuroprotective agents. The knowledge that multiple mechanisms contribute to neuronal injury in ischaemia have led to the general recognition that a single drug treatment is unlikely to be beneficial in the treatment of cerebral ischaemia. 3. AM-36 [1-(2-(4-chlorophenyl)-2-hydroxy)ethyl-4-(3,5-bis(1,1-dimethyl)-4-hydroxyphenyl)methylpiperazine] is one of a series of hybrid molecules designed to incorporate multiple neuroprotective mechanisms within the one structure. Primary screening tests demonstrated that AM-36 inhibited binding to the polyamine site of glutamate receptors, blocked neuronal sodium channels and had potent anti-oxidant activity. In neuronal cell cultures, AM-36 inhibited toxicity induced by N-methyl-D-aspartate (NMDA) and the sodium channel opener veratridine and, in addition, inhibited veratridine-induced apoptosis.
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