BRL 52537 hydrochloride is a potent and selective agonist of κ/μ-opioid receptor with Ki value of 0.24 nM for κ-opioid receptor [1].
The κ-opioid receptor (KOR) is a type of opioid receptor for opioid peptide dynorphin and controls addiction. Also, KOR plays an important role in stress, anxiety, anhedonia, depression and increased drug-seeking behavior.
BRL 52537 hydrochloride is a potent and selective κ/μ-opioid receptor agonist. In the mouse tail flick model, BRL 52537 showed antinociception with ED50 value of 0.05 mg/kg, which was 25 times more potent than morphine [1]. In WT male mice with middle cerebral artery occlusion, BRL 52537 significantly decreased infarct volumes at 72 h of reperfusion. However, BRL 52537 had no effect in neuronal NO synthase null mutants (nNOS-/-) mice or in the WT female mice. These results suggested that BRL 52537 exhibited neuroprotection through inhibition of ischemia-evoked NO production and nNOS activity [2]. In adult rat dorsal root ganglia (DRGs), BRL 52537 inhibited tetrodotoxin-resistant (TTX-r) sodium currents in an opioid receptor-independent way, which also contributed to the antinociceptive effects [3]. In rats with cerebral ischemia/reperfusion (I/R) injury, BRL52537 inhibited neuronal apoptosis and brain damage. Also, BRL52537 increased the level of phosphorylated STAT3 and reduced caspase-3 expression [4].
References:
[1]. Vecchietti V, Giordani A, Giardina G, et al. (2S)-1-(arylacetyl)-2-(aminomethyl)piperidine derivatives: novel, highly selective kappa opioid analgesics. J Med Chem, 1991, 34(1): 397-403.
[2]. Zeynalov E, Nemoto M, Hurn PD, et al. Neuroprotective effect of selective kappa opioid receptor agonist is gender specific and linked to reduced neuronal nitric oxide. J Cereb Blood Flow Metab, 2006, 26(3): 414-420.
[3]. Su X, Castle NA, Antonio B, et al. The effect of kappa-opioid receptor agonists on tetrodotoxin-resistant sodium channels in primary sensory neurons. Anesth Analg, 2009, 109(2): 632-640.
[4]. Fang S, Xu H, Lu J, et al. Neuroprotection by the kappa-opioid receptor agonist, BRL52537, is mediated via up-regulating phosphorylated signal transducer and activator of transcription-3 in cerebral ischemia/reperfusion injury in rats. Neurochem Res, 2013, 38(11): 2305-2312.