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.
(-)-(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.
Mauler
Frank
F
CNS Research, Bayer AG, Business Group Pharma, Aprather Weg 18a, 42096 Wuppertal, Germany. frank.mauler.fm@bayer-ag.de
Mittendorf
Joachim
J
Horváth
Ervin
E
De Vry
Jean
J
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology; D003511:Cyclohexanols / Q000494:pharmacology; D004192:Discrimination, Psychological / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006408:Hematoma, Subdural / Q000188:drug therapy; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D020768:Middle Cerebral Artery / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013451:Sulfonic Acids / Q000494:pharmacology / Q000627:therapeutic use
C459384:3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate; C469526:Cnr2 protein, rat; D003511:Cyclohexanols; D007189:Indans; D018696:Neuroprotective Agents; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013451:Sulfonic Acids; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D013385:Succinate Dehydrogenase