Characterization of the diarylether sulfonylester (-)-(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.

Abstract

(-)-(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) = 0.46-1.85 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-[gamma(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 microg/kg, i.v.); whereas in rats trained to discriminate the CB1/CB2 receptor agonist (-)-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 microg/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.

• Authors: Frank Mauler, Joachim Mittendorf, Ervin Horváth, Jean De Vry
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 302 Issue 1 Pg. 359-68 (Jul 2002) ISSN: 0022-3565 [Print] United States
• PMID: 12065738 (Publication Type: Journal Article)

Chemical References

• 3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate
• Cnr2 protein, rat
• Cyclohexanols
• Indans
• Neuroprotective Agents
• Receptor, Cannabinoid, CB2
• Receptors, Cannabinoid
• Receptors, Drug
• Sulfonic Acids
• Guanosine 5'-O-(3-Thiotriphosphate)
• 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
• Succinate Dehydrogenase

Topics

• Animals
• Binding, Competitive (drug effects)
• Body Temperature (drug effects)
• Brain Injuries (drug therapy, pathology)
• Brain Ischemia (drug therapy, pathology)
• Cyclohexanols (pharmacology)
• Discrimination, Psychological (drug effects)
• Guanosine 5'-O-(3-Thiotriphosphate) (pharmacology)
• Hematoma, Subdural (drug therapy)
• Indans (pharmacology, therapeutic use)
• Male
• Middle Cerebral Artery (physiology)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Rats
• Rats, Long-Evans
• Rats, Wistar
• Receptor, Cannabinoid, CB2
• Receptors, Cannabinoid
• Receptors, Drug (agonists)
• Signal Transduction (drug effects)
• Succinate Dehydrogenase (metabolism)
• Sulfonic Acids (pharmacology, therapeutic use)