BRL 52537 hydrochloride

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.

Neuroprotective effect of selective kappa opioid receptor agonist is gender specific and linked to reduced neuronal nitric oxide.[Pubmed:16049424]

J Cereb Blood Flow Metab. 2006 Mar;26(3):414-20.

We have previously shown that treatment with selective kappa-opioid receptor agonist BRL 52537 hydrochloride [(+/-)-1-(3,4-dichlorophenyl) acetyl-2-(1-pyrrolidinyl) methylpiperidine] (1) has a long therapeutic window for providing ischemic neuroprotection and (2) attenuates ischemia-evoked nitric oxide (NO) production in vivo in rats. Neuronally derived NO has been shown to be deleterious in the male, but not in the female, rodent model of focal ischemic stroke. We sought to determine if the agent fails to protect ischemic brain when neuronal NO synthase (nNOS) is genetically deleted in male, but not female, mice. Halothane-anesthetized adult male and female nNOS null mutants (nNOS(-/-)) and the genetically matched wildtype (WT) strain were subjected to transient (2 h) middle cerebral artery occlusion by the intraluminal filament technique. Vehicle or BRL 52537 treatment with continuous intravenous infusion was instituted at the onset of reperfusion and continued for 22 h. In WT male mice, infarct volumes measured at 72 h of reperfusion were robustly decreased with BRL 52537 treatment. In contrast, BRL 52537 did not decrease infarct volume in male nNOS(-/-) mice. BRL 52537 had no effect in the WT or nNOS(-/-) female mice. These data support that BRL 52537's mechanism of neuroprotection in vivo is through attenuation of nNOS activity and ischemia-evoked NO production. Neuroprotective effects of BRL 52537 are lost in the male when nNOS is not present; therefore, BRL 52537 likely acts upstream from NO generation and its subsequent neurotoxicity.

Ischemic neuroprotection with selective kappa-opioid receptor agonist is gender specific.[Pubmed:15933260]

Stroke. 2005 Jul;36(7):1557-61.

BACKGROUND AND PURPOSE: We demonstrated previously that treatment with selective kappa-opioid receptor (KOR) agonist BRL 52537 hydrochloride [(+/-)-1-(3,4-dichlorophenyl) acetyl-2-(1-pyrrolidinyl) methylpiperidine] (1) has a long therapeutic window for providing ischemic neuroprotection, and (2) attenuates ischemia-evoked NO production in vivo in rats. Neuronally derived NO has been shown to be deleterious in the male but not in the female rodent model of focal ischemic stroke. We tested the hypothesis that BRL provides significant neuroprotection from transient focal ischemia in male but not in female rats. METHODS: Halothane-anesthetized adult male and female Wistar rats (250 to 275 g) were subjected to 2 hours of middle cerebral artery occlusion (MCAO) by the intraluminal suture technique. Adequacy of MCAO and reperfusion was monitored with laser-Doppler flowmetry over the ipsilateral parietal cortex. In the first experiment, male and female rats were treated in a blinded randomized fashion with vehicle saline or 1 mg/kg per hour BRL infusion started at the onset of reperfusion and continued for 22 hours. In the second experiment, ovariectomized (OVX) female rats were treated with vehicle or BRL. Infarct volume in the cortex and caudoputamen (CP) complex was assessed by triphenyl tetrazolium chloride staining at 72 hours after MCAO. RESULTS: Infarct volume (percentage of ipsilateral structure; mean+/-SEM) was attenuated significantly in male rats with BRL treatment (cortex 23+/-5%; CP 44+/-6%; n=15) compared with vehicle-treated male rats (cortex 38+/-4%; CP 66+/-4%; n=15) but not in female rats (BRL-cortex 26+/-6; CP 55+/-8%; vehicle-cortex 26+/-5; CP 62+/-5%; n=10 each). Neurologic deficit score was improved in BRL-treated male rats but not in female rats. Infarct volume was not different in OVX female rats treated with vehicle or BRL. CONCLUSIONS: These data: (1) demonstrate that this dose of selective KOR agonist provides ischemic neuroprotection in male but not female rats, (2) demonstrate that the lack of protection by BRL is not attributable to circulating ovarian hormones, and (3) highlight the importance of using animal models of both sexes in preclinical studies of experimental ischemia.

Prolonged opportunity for ischemic neuroprotection with selective kappa-opioid receptor agonist in rats.[Pubmed:15031456]

Stroke. 2004 May;35(5):1180-5.

BACKGROUND AND PURPOSE: We have previously demonstrated that pretreatment with selective kappa-opioid agonist BRL 52537 hydrochloride [(+/-)-1-(3,4-dichlorophenyl) acetyl-2-(1-pyrrolidinyl) methylpiperidine], provides ischemic neuroprotection following transient focal ischemia in rats. The present study was undertaken to a) define "therapeutic opportunity" for ischemic neuroprotection with BRL 52537, and b) determine if BRL 52537 attenuates ischemia-evoked efflux of dopamine and its metabolites in the striatum in vivo following transient focal ischemia. METHODS: Using the intraluminal filament technique, halothane-anesthetized male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAO). In a blinded, randomized fashion, rats were treated with saline (vehicle) or 1 mg/Kg/hr BRL 52537 infusion for 22 hours, initiated at onset, 2, 4, or 6 hours of reperfusion (Rep). In a separate set of experiments utilizing in vivo microdialysis, extracellular levels of dopamine and its metabolites were determined in the striatum during 2 hours of MCAO and 3 hours of reperfusion. RESULTS: Infarct volume (% of contralateral structure; mean +/-SEM) in cortex was significantly attenuated when BRL 52537 was administered at reperfusion (22+/-6%), 2 hours (21+/-6%), and 4 hours (18+/-5%) compared with controls (39+/-5%). In striatum, infarct volume was significantly attenuated when BRL 52537 was administered at reperfusion (38+/-9%), 2 hours (40+/-8%), 4 hours (50+/-8%), and 6 hours (46+/-9%) as compared with controls (70+/-4%). A 6- to 8-fold increase in dopamine in microdialysates occurred within 40 minutes of MCAO. Pretreatment with BRL 52537 did not alter microdialysate levels of dopamine or its metabolites in the striatum during MCAO and early reperfusion, as compared with saline controls. CONCLUSIONS: These data demonstrate that BRL 52537 provides robust ischemic neurprotection with a long therapeutic opportunity (at least 6 hours) without altering ischemia-evoked efflux of dopamine (DA) and its metabolites in striatum during ischemia and early reperfusion.

Kappa-opioid receptor selectivity for ischemic neuroprotection with BRL 52537 in rats.[Pubmed:14633559]

Anesth Analg. 2003 Dec;97(6):1776-83.

UNLABELLED: Kappa-opioid receptors (KOR) have been implicated in neuroprotection from ischemic neuronal injury, but less work has been performed with transient focal cerebral ischemia to determine the role of KOR during reperfusion. We tested the effects of a selective and specific KOR agonist, BRL 52537 hydrochloride [(+/-)-1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine], and the standard KOR antagonist, nor-binaltorphimine dihydrochloride [nor-BNI; 17,17'-(dicyclopropylmethyl)-6,6',7,7'-6,6'-imino-7,7'-binorphinan-3,4',14,14'-te trol], on functional and histological outcome after transient focal ischemia in the rat. By use of the intraluminal filament technique, halothane-anesthetized adult male Wistar rats were subjected to 2 h of middle cerebral artery occlusion confirmed by laser Doppler flowmetry. In a blinded, randomized fashion, rats were treated with 1). saline (vehicle) 15 min before reperfusion followed by saline at reperfusion for 22 h, 2). saline 15 min before reperfusion followed by BRL 52537 (1 mg x kg(-1) x h(-1)) at reperfusion for 22 h, 3). saline 15 min before reperfusion followed by nor-BNI (1 mg x kg(-1) x h(-1)) at reperfusion for 22 h, or 4) nor-BNI (1 mg/kg) 15 min before reperfusion followed by BRL 52537 (1 mgx kg(-1)x h(-1)) and nor-BNI (1 mg x kg(-1) x h(-1)) at reperfusion for 22 h. Infarct volume (percentage of ipsilateral structure) analyzed at 4 days of reperfusion was significantly attenuated in saline/BRL 52537 rats (n = 8; cortex, 10.2% +/- 4.3%; caudoputamen [CP], 23.8% +/- 6.7%) (mean +/- SEM) compared with saline/saline treatment (n = 8; cortex, 28.6% +/- 4.9%; CP, 53.3% +/- 5.8%). Addition of the specific KOR antagonist nor-BNI to BRL 52537 completely prevented the neuroprotection (n = 7; cortex, 28.6% +/- 5.3%; CP, 40.9% +/- 6.2%) conferred by BRL 52537. BRL 52537 did not produce postischemic hypothermia. These data demonstrate that KORs may provide a therapeutic target during early reperfusion after ischemic stroke. IMPLICATIONS: The neuroprotective effect of selective kappa-opioid agonists in transient focal ischemia is via a selective action at the kappa-opioid receptors.

Neuroprotective kappa-opioid receptor agonist BRL 52537 attenuates ischemia-evoked nitric oxide production in vivo in rats.[Pubmed:12738895]

Stroke. 2003 Jun;34(6):1533-8.

BACKGROUND AND PURPOSE: Kappa-opioid receptors (KOR) have been implicated in neuroprotection from ischemic neuronal injury. We tested the effects of a selective and specific KOR agonist, BRL 52537 hydrochloride [(+/-)-1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl) methylpiperidine], on infarct volume and nitric oxide production after transient focal ischemia in the rat. METHODS: With the use of the intraluminal filament technique, halothane-anesthetized male Wistar rats (weight, 250 to 300 g) were subjected to 2 hours of focal cerebral ischemia confirmed by Doppler flowmetry. In a blinded randomized fashion, rats were treated with intravenous saline or 1 mg/kg per hour BRL 52537 infusion, initiated 15 minutes before occlusion and maintained until 2 hours of reperfusion. In a second experiment, rats were treated during reperfusion with saline or 1 mg/kg per hour BRL 52537, initiated at onset of reperfusion and continued for 22 hours. In a final experiment, in vivo striatal nitric oxide production was estimated via microdialysis by quantification of citrulline recovery after labeled arginine infusion in striatum of intravenous BRL 52537- or saline-treated rats. RESULTS: In rats treated with BRL 52537 during ischemia and early reperfusion, infarct volume was significantly attenuated in cortex (16+/-6% versus 40+/-7% of ipsilateral cortex in saline group) and in caudoputamen (30+/-8% versus 66+/-6% of ipsilateral caudoputamen in saline group). Infarct volume was also reduced by treatment administered only during reperfusion in cortex (19+/-8% in BRL 52537 group [n=10] versus 38+/-6% in saline group) and in caudoputamen (35+/-9% versus 66+/-4% in saline group). BRL 52537 treatment markedly attenuated NO production in ischemic striatum compared with saline-treated controls. CONCLUSIONS: These data demonstrate that (1) the selective KOR agonist BRL 52537 provides significant neuroprotection from focal cerebral ischemia when given as a pretreatment or as a posttreatment and (2) attenuation of ischemia-evoked nitric oxide production in vivo may represent one mechanism of ischemic neuroprotection.

(2S)-1-(arylacetyl)-2-(aminomethyl)piperidine derivatives: novel, highly selective kappa opioid analgesics.[Pubmed:1846921]

J Med Chem. 1991 Jan;34(1):397-403.

This paper describes the synthesis and structure-activity relationships as kappa opioid analgesics of a novel class of 1-(arylacetyl)-2-(aminomethyl)piperidine derivatives. The active conformation of the pharmacophore, with a torsional angle (N1C2C7N8) of 60 degrees, was defined with computational studies and 1H NMR. A quantitative structure-activity relationship study of the arylacetic moiety substitution indicated that the presence of an electron-withdrawing and lipophilic substituent in para and/or meta positions is required for good analgesic activity and kappa affinity. The lead compounds (2S)-1-[(3,4-dichlorophenyl)acetyl]-2-(pyrrolidin-1-ylmethyl )piperidine hydrochloride and (2S)-1-[4-(trifluoromethyl)phenyl]acetyl]-2-(pyrrolidin-1-ylmet hyl) piperidine hydrochloride are the most kappa/mu selective (respectively 6500:1 and 4100:1) and among the most potent (Ki kappa 0.24 and 0.57 nM, respectively) kappa ligands identified so far. In the mouse tail flick model of antinociception, compound 14 (ED50 = 0.05 mg/kg sc) was 25 times more potent than morphine and 16 times more potent than the standard kappa ligand U-50488.