Details
| Stereochemistry | RACEMIC |
| Molecular Formula | C13H17N3.C4H4O4 |
| Molecular Weight | 331.3663 |
| Optical Activity | ( + / - ) |
| Defined Stereocenters | 0 / 1 |
| E/Z Centers | 1 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
OC(=O)\C=C/C(O)=O.CC1N(CC2=NCCN2)CC3=CC=CC=C13
InChI
InChIKey=DDIQGSUEJOOQQQ-BTJKTKAUSA-N
InChI=1S/C13H17N3.C4H4O4/c1-10-12-5-3-2-4-11(12)8-16(10)9-13-14-6-7-15-13;5-3(6)1-2-4(7)8/h2-5,10H,6-9H2,1H3,(H,14,15);1-2H,(H,5,6)(H,7,8)/b;2-1-
BRL-44408, a potent (Ki=8.5 nM) and selective (>50-fold) α2A-adrenoceptor antagonist (KB=7.9 nM). BRL-44408 revealed antidepressant- and analgesic-like activity through selective alpha2A-adrenoceptor antagonism. Preclinical characterization of the neurochemical and behavioural profile of BRL-44408 suggests that selective antagonism of alpha2A-adrenoceptors may represent an effective treatment strategy for mood disorders and visceral pain. BRL-44408 increases hippocampal noradrenalin release following systemic administration. BRL-44408 has potential therapeutic application in the treatment of extrapyramidal side effects produced by some antipsychotic medications.
CNS Activity
Curator's Comment: In rats, BRL-44408 penetrated the central nervous system resulting in peak brain and plasma concentrations of 586 ng/g and 1124 ng/ml, respectively. In the forced swim test and schedule-induced polydipsia assay, BRL-44408 produced an antidepressant-like response by dose-dependently decreasing immobility time and adjunctive water intake, respectively, while in a model of visceral pain, BRL-44408 exhibited analgesic activity by decreasing para-phenylquinone (PPQ)-induced abdominal stretching.
Originator
Approval Year
PubMed
| Title | Date | PubMed |
|---|---|---|
| Novel alpha 2-adrenoceptor antagonists show selectivity for alpha 2A- and alpha 2B-adrenoceptor subtypes. | 1989 Sep 22 |
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| Presynaptic alpha 2-autoreceptors in brain cortex: alpha 2D in the rat and alpha 2A in the rabbit. | 1993 Jul |
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| The novel alpha-2 adrenergic radioligand [3H]-MK912 is alpha-2C selective among human alpha-2A, alpha-2B and alpha-2C adrenoceptors. | 1994 Dec |
|
| A comparative study of the reversal by different alpha 2-adrenoceptor antagonists of the central sympatho-inhibitory effect of clonidine. | 1996 Feb |
|
| Interaction of formamidine pesticides with the presynaptic alpha(2)-adrenoceptor regulating. | 2001 May 1 |
|
| Vascular actions of 3,4-methylenedioxymethamphetamine in alpha(2A/D)-adrenoceptor knockout mice. | 2002 Dec 13 |
|
| Investigation of postjunctional alpha1- and alpha2-adrenoceptor subtypes in vas deferens from wild-type and alpha(2A/D)-adrenoceptor knockout mice. | 2003 Mar |
|
| Alpha-2 agonist-induced memory impairment is mediated by the alpha-2A-adrenoceptor subtype. | 2004 Aug 31 |
|
| Dexmedetomidine produces its neuroprotective effect via the alpha 2A-adrenoceptor subtype. | 2004 Oct 11 |
|
| Role of alpha2A-adrenoceptors in the effects of MDMA on body temperature in the mouse. | 2005 Sep |
|
| Alpha2-adrenoceptor stimulation transforms immune responses in neuritis and blocks neuritis-induced pain. | 2005 Sep 28 |
|
| Effects of MDMA, MDA and MDEA on blood pressure, heart rate, locomotor activity and body temperature in the rat involve alpha-adrenoceptors. | 2006 Apr |
|
| The involvement of peripheral alpha 2-adrenoceptors in the antihyperalgesic effect of oxcarbazepine in a rat model of inflammatory pain. | 2007 Nov |
|
| Therapeutic potential of alpha2 adrenoceptor antagonism for antipsychotic-induced extrapyramidal motor disorders. | 2009 Apr 24 |
Sample Use Guides
Rats: in the FST (forced swim test), acute treatment with BRL-44408 (3–30 mg/
kg i.p.) produced a significant decrease in immobility
time relative to vehicle-treated animals. BRL-44408 at both 10 and 30 mg/kg
significantly decreased immobility time by 30% and 49%, respectively. Acute pretreatment with BRL-44408 (1–30 mg/kg,
i.p.) produced a dose-dependent reversal of PPQinduced
stretching behaviour relative to vehicle. BRL-44408 at 10 and 30 mg/kg produced a
significant blockade of PPQ-induced stretching by
32% and 52%, respectively.
Route of Administration:
Intraperitoneal
In Vitro Use Guide
Curator's Comment: Subtype-selective antagonists were used to determine the subtype of alpha2-adrenoceptor controlling noradrenaline release in rat locus coeruleus. Noradrenaline release was measured in locus coeruleus slices using fast cyclic voltammetry at carbon fibre microelectrodes.
On long stimulation trains (40 pulses, 20 Hz), the alpha2A-adrenoceptor selective antagonist BRL-44408 at 100 nM and 1 uM significantly increased stimulated noradrenaline release.
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96KFS04PNM
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10382026
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681806-46-2
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ACTIVE MOIETY
SUBSTANCE RECORD
