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 (Ki = 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-[γ35S]-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 antagonistN-(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.
Footnotes
- Abbreviations:
- BAY 38-7271
- (−)-(R)-3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate
- Bmax
- maximal specific binding
- CB1 receptor
- cannabinoid receptor subtype 1
- CB2 receptor
- cannabinoid receptor subtype 2
- CP 55,940
- (−)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol
- CL
- confidence limits
- Δ9-THC
- (−)-Δ9-tetrahydrocannabinol
- [35S]GTPγS
- 5-[γ35S]-thiophosphate triethylammonium salt
- HU-210
- (−)-11-OH-Δ8-tetrahydrocannabinol-dimethylheptyl
- Kd
- equilibrium dissociation constant
- Ki
- dissociation constant for inhibitor binding
- SDH
- acute subdural hematoma
- SR 141716A
- N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride
- T1/2
- half-life time
- TBI
- traumatic brain injury
- pMCA-O
- permanent focal middle cerebral artery occlusion
- WIN 55,212-2
- (R)-4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphtalenylcarbonyl)-6H-pyrrolo[3,2,1-ij]quinolin-6-one
- Received December 17, 2001.
- Accepted March 21, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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