Background:

BRL 44408 maleate is a selective antagonist of α2A-adrenoceptor with Ki values of 1.7 and 144.5 nM for α2A- and α2B-adrenoceptors, respectively.

α2A-adrenoceptor is a G-protein coupled receptor. α2-adrenergic receptors include three subtypes: α2A, α2B and α2C, which play an important role in regulating neurotransmitter release from adrenergic neurons in the central nervous system and from sympathetic nerves.

BRL 44408 maleate is a selective α2A-adrenoceptor antagonist. In rat brain, BRL 44408 inhibited the binding of 5-HTIA receptor radioligands 8-OH-DPAT and RX 821002 to cortical membranes with Ki values of 199 and 338 nM respectively, which suggested that BRL 44408 recognized 5-HT1A receptor [1].

In wild type and monoamine oxidase-A knockout (MAO-A KO) mice, BRL 44408 (100 nM) inhibited the effect of dexmedetomidine, the α2 agonist. BRL 44408 (100 nM) increased evoked noradrenaline (NA) efflux in MAO-A KO mice. In wild type mice, BRL 44408 antagonized the agonist effect of dexmedetomidine with pKB value of 7.75, which inhibited locus coeruleus (LC) cell firing with EC50 value of 2.6 nM [2]. In the forced swim test, BRL 44408 reduced immobility time. In schedule-induced polydipsia assay, BRL 44408 increased adjunctive water intake, which suggested that BRL 44408 exhibited antidepressant-like response. In a visceral pain model, BRL 44408 exhibited analgesic activity [3].

参考文献:
[1].  Meana JJ, Callado LF, Pazos A, et al. The subtype-selective alpha 2-adrenoceptor antagonists BRL 44408 and ARC 239 also recognize 5-HT1A receptors in the rat brain. Eur J Pharmacol, 1996, 312(3): 385-388.
[2].  Owesson CA, Seif I, McLaughlin DP, et al. Different alpha(2) adrenoceptor subtypes control noradrenaline release and cell firing in the locus coeruleus of wildtype and monoamine oxidase-A knockout mice. Eur J Neurosci, 2003, 18(1): 34-42.
[3].  Dwyer JM, Platt BJ, Rizzo SJ, et al. Preclinical characterization of BRL 44408: antidepressant- and analgesic-like activity through selective alpha2A-adrenoceptor antagonism. Int J Neuropsychopharmacol, 2010, 13(9): 1193-1205.