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ABSTRACT(Ϫ)-(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 ϭ 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- [␥ 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 ϭ 6 g/kg, i.v.); whereas in rats trained to discriminate the CB1/ CB2 receptor agonist (Ϫ)-cis-3-[2-hydroxy-4(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP 55,940; 0.03 mg/kg, i.p.) from vehicle, BAY 38-7271 induced complete generalization (3 g/kg, i.v.). In both in vivo models, a specific CB1 receptor-mediated mechanism was confirmed by demonstrating that the effects of CP 55, were blocked by pretreatment with the selective CB1 receptorIn 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.Historical and anecdotal reports suggest that Cannabis sativa has a wide spectrum of therapeutic effects, including analgesic, appetite stimulating, anti-emetic, antiglaucomic, and antispastic effects (Joy et al., 1999). Scientific studies on the pharmacology of cannabis were advanced considerably by the identification of the cannabinoid ⌬ 9 -THC as the major active constituent of cannabis predominantly responsible for its therapeutic and psychoactive effects (Gaoini and Mechoulam, 1964), the cloning of the centrally located CB1 receptor (Matsuda et al., 1990) and the peripherally located CB2 receptor (Munro et al., 1993), and the identification of selective CB1 and CB2 receptor antagonists (for review, see Barth, 1998). Both receptors are negatively coupled to adenylate cyclase through heterotrimeric G i/o proteins (Pertwee, 1997). The CB1 receptor was found to be also negatively coupled to N-and P/Q-type voltage sensitive Ca 2ϩ -and Dtype K ϩ channels and positively coupled to A-type and inward-rectifying K ϩ channels (Pertwee, 1997;Mu et al., 1999). Activation of CB1 receptors leads to cell hyperpolarization and inhibition of neurotransmitter release (Kim and Thayer, 2000;Gerdeman an...

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Early deterioration and death after brain injury is often the result of oedema in the injured and peri-lesional tissue. So far, no pharmacotherapy is available that exhibits significant brain oedema-reducing efficacy in patients. We selected two low molecular weight compounds from different chemical classes, a triazole (1-[(2-chlorophenyl)diphenylmethyl]-1,2,3-triazole) and a cyclohexadiene (methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-1,4,7-tetrahydroisobenzofuran-5-carboxylate) to characterize their pharmacological properties on KCNN4 channels (intermediate/small conductance calcium-activated potassium channel, subfamily N, member 4) in vitro as well as in vivo. In vitro we replaced potassium by rubidium (Rb+) and determined Rb+ fluxes evoked by 10 micro m of the calcium ionophore A23187 on C6BU1 rat glioma cells. Compared with known KCNN4 blockers, such as clotrimazole (IC50=360 +/- 12 nm) and charybdotoxin (IC50=3.3 +/- 1.9 nm), the triazole and cyclohexadiene were considerably more potent than clotrimazole and displayed similar potencies (IC50=12.1 +/- 8.8 and 13.3 +/- 4.7 nm, respectively). In the rat acute subdural haematoma model, both the triazole and cyclohexadiene displayed reduction of brain water content (-26% at 0.3 mg/kg and -24% at 0.01 mg/kg) and reduction of the intracranial pressure (-46% at 0.1 mg/kg and -60% at 0.003 mg/kg) after 24 h when administered as a 4-h infusion immediately after brain injury. When infarct volumes were determined after 7 days, the triazole as well as the cyclohexadiene displayed strong neuroprotective efficacy (-52% infarct volume reduction at 1.2 mg/kg and -43% at 0.04 mg/kg, respectively). It is concluded that blockade of KCNN4 channels is a new pharmacological approach to attenuate acute brain damage caused by traumatic brain injury.