Loading…
Characterization of the Diarylether Sulfonylester (â)-(R)-3-(2-Hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate (BAY 38-7271) as a Potent Cannabinoid Receptor Agonist with Neuroprotective Properties
(â)-( R )-3-(2-Hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate (BAY 38-7271) is a new high-affinity cannabinoid receptor subtype 1 (CB1 receptor) ligand ( K i = 0.46â1.85 nM; rat brain, human cortex, or recombinant human CB1 receptor), structurally unrelated to any cannabinoid rece...
Saved in:
Published in: | The Journal of pharmacology and experimental therapeutics 2002-07, Vol.302 (1), p.359-368 |
---|---|
Main Authors: | , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Summary: | (â)-( R )-3-(2-Hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate (BAY 38-7271) is a new high-affinity cannabinoid receptor
subtype 1 (CB1 receptor) ligand ( K i = 0.46â1.85 nM; rat brain, human cortex, or recombinant human CB1 receptor), structurally unrelated to any cannabinoid receptor
ligand known so far. BAY 38-7271 was characterized as a CB1 receptor agonist in 5-[γ 35 S]-thiophosphate triethylammonium salt binding assays using rat or human CB1 receptors. In the rat hypothermia assay, BAY
38-7271 induced a dose-dependent reduction in body temperature (minimal effective dose = 6 μg/kg, i.v.); whereas in rats trained
to discriminate the CB1/CB2 receptor agonist (â)- cis -3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]- trans -4-(3-hydroxypropyl) cyclohexanol (CP 55,940; 0.03 mg/kg, i.p.) from vehicle, BAY 38-7271 induced complete generalization
(3 μg/kg, i.v.). In both in vivo models, a specific CB1 receptor-mediated mechanism was confirmed by demonstrating that the
effects of CP 55,940 and BAY 38-7271 were blocked by pretreatment with the selective CB1 receptor antagonist N -(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride. In the rat traumatic
brain injury model, BAY 38-7271 demonstrated highly potent and efficient neuroprotective properties when administered as a
4-h infusion immediately after induction of subdural hematoma (70% infarct volume reduction at 100 ng/kg/h). Even when applied
with a 3-h delay, a significant neuroprotective efficacy could be observed (59% infarct volume reduction at 300 ng/kg/h).
The neuroprotective potential of BAY 38-7271 was confirmed in a rat model of focal cerebral ischemia induced by permanent
occlusion of the middle cerebral artery. It is concluded that the CB1/CB2 receptor agonist BAY 38-7271 shows pronounced neuroprotective
properties that do not result from drug-induced hypothermia and that occur in a dose range devoid of typical cannabinoid-like
side effects. |
---|---|
ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.302.1.359 |