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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 302; no. 1; pp. 359 - 368
• Main Authors: Mauler, Frank, Mittendorf, Joachim, Horváth, Ervin, De Vry, Jean
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.07.2002
• Subjects: Animals; Binding, Competitive - drug effects; Body Temperature - drug effects; Brain Injuries - drug therapy; Brain Injuries - pathology; Brain Ischemia - drug therapy; Brain Ischemia - pathology; Cyclohexanols - pharmacology; Discrimination (Psychology) - drug effects; Guanosine 5'-O-(3-Thiotriphosphate) - pharmacology; Hematoma, Subdural - drug therapy; Indans - pharmacology; Indans - therapeutic use; Male; Middle Cerebral Artery - physiology; Neuroprotective Agents - pharmacology; Neuroprotective Agents - 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; Sulfonic Acids - therapeutic use
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.302.1.359

(−)-( 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-[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 (−)- 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.