Anti-tremor activity of talipexole produced by selective dopamine D2 receptor stimulation in cynomolgus monkeys with unilateral lesions in the ventromedial tegmentum.
The anti-tremor activity of talipexole (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine dihydrochloride, B-HT 920 CL2, Domin), a non-ergot dopamine D2 receptor agonist which possesses alpha 2-adrenoceptor agonistic and 5-HT3 receptor antagonistic properties, was examined in monkeys with a unilateral lesion in the ventromedial tegmentum. Talipexole dose dependently suppressed the tremor and had ED50 values of 34 micrograms/kg s.c. and 84 micrograms/kg p.o. The anti-tremor effect of talipexole occurred at much lower doses than that of an ergot dopamine receptor agonist, bromocriptine (2-bromo-alpha-ergocryptine mesilate, ED50; 2.5 mg/kg s.c.), and talipexole acted synergistically in combination with L-DOPA (3,4-dihydroxyphenylalanine). In ventromedial tegmentum-lesioned monkeys, anti-tremor doses of talipexole did not cause emetic behavior, but had sedative effects. Conversely, monkeys given bromocriptine exhibited oral movement, salivation and vomiting when anti-tremor effects were observed, but not marked sedative behavior at any of the doses investigated. During repeated administration of talipexole (a daily dose of 50 micrograms/kg s.c. for 21 days), the extent and duration of the anti-tremor effect did not change, but those of the sedative effect decreased gradually. The anti-tremor effect of talipexole was significantly suppressed by sulpiride, but not by SCH 23390 (7-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) or yohimbine, while the sedative effect was inhibited by sulpiride and yohimbine. The main metabolites of talipexole had no anti-tremor or sedative effects. These results indicate that talipexole exerts its anti-tremor activity via selective dopamine D2 receptor stimulation.
Kohno
Y
Y
Product Management Department, Nippon Boehringer Ingelheim Co., Ltd., Kawanishi, Japan.
Fukuzaki
K
K
Kitahara
K
K
Koja
T
T
D000284:Administration, Oral; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001971:Bromocriptine / Q000627:therapeutic use; D015259:Dopamine Agents / Q000627:therapeutic use; D018491:Dopamine Agonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007279:Injections, Subcutaneous; D007980:Levodopa / Q000627:therapeutic use; D008252:Macaca fascicularis; D008297:Male; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D013681:Tegmentum Mesencephali / Q000187:drug effects*; D014202:Tremor / Q000188:drug therapy*
D000316:Adrenergic alpha-Agonists; D001381:Azepines; D015259:Dopamine Agents; D018491:Dopamine Agonists; D065127:Dopamine D2 Receptor Antagonists; D006993:Hypnotics and Sedatives; D017448:Receptors, Dopamine D2; D001971:Bromocriptine; D007980:Levodopa; C024763:talipexole