Interaction of dexanabinol (HU-211), a novel NMDA receptor antagonist, with the dopaminergic system.
The interaction of 7-hydroxy-delta6-tetrahydrocannabinol 1,1-dimethylheptyl (Dexanabinol: HU-211), a novel NMDA receptor antagonist, with the dopaminergic system was examined using in vitro and in vivo systems. HU-211 (50 or 100 microM) inhibited the binding of [3H]R(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepi n-7-ol hydrochloride ([3H]SCH-23390), a dopamine D1 receptor antagonist, by 29.7 +/- 1.8% and 52.7 +/- 6.3%, respectively. HU-211 10 microM, like the dopamine D1 receptor agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF-38393), enhanced the conversion of [3H]adenine to cyclic AMP (cAMP) (51.8 +/- 29.7% and 35.6 +/- 21.5% over control, respectively). The HU-211-induced increase was not inhibited by SCH-23390. HU-211 together with the dopamine D1 receptor agonist caused a synergistic elevation (314.7 +/- 14.3%). HU-211 reduced the catalepsy induced by dopamine receptor antagonists. At 10 mg/kg, HU-211 significantly (P < 0.001) reduced the catalepsy time induced by D1, D2 and non-selective dopamine receptor antagonists. Overall, the results of the present study demonstrate that HU-211 interacts with the dopaminergic system and enhances activity at the dopamine D1 receptor level. This activity may have implications in diseases involving the dopaminergic system, such as Parkinson's disease.
Striem
S
S
Pharmos Corp., Kiryat Weizmann, Rehovot, Israel.
Bar-Joseph
A
A
Berkovitch
Y
Y
Biegon
A
A
D000818:Animals; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000633:toxicity; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology*
D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D013759:Dronabinol; D000242:Cyclic AMP; C062018:HU 211