Investigations with the novel non-opioid analgesic flupirtine in regard to possible benzodiazepine-like abuse inducing potential.
Flupirtine (D-9998, Katadolon, CAS 56995-20-1); CAS 56995-20-1), a novel non-opioid analgesic was investigated for possible benzodiazepine-like activities. In receptor binding studies flupirtine and its metabolite were found to reveal no affinity for specific 3H-flunitrazepam binding up to a concentration of 10 mumol/l. In drug discrimination studies, rats were trained to discriminate the novel analgesic flupirtine (10 mg/kg i.p.) from no drug (NaCl 0.9%) under a two-choice fixed-ratio 5 shock-termination schedule. Flupirtine yielded a dose-response curve with an ED50 of 3.9 mg/kg i.p. In generalization tests with a benzodiazepine-type compound lorazepam (0.3 mg/kg, i.p.) did not generalize to the flupirtine training dose. In physical dependence studies using rats, during and after chronic oral administration of flupirtine (2 x 80 mg/kg p.o.) over 45 days no signs of benzodiazepine- and opiate-like physical dependence were observed in rats after withdrawal of the drug. In contrast diazepam (2 x 5 bzw. 2 x 10 mg/kg p.o.) induced typical symptoms of physical dependence. A significant weight loss of the codeine treated animals (2 x 60 mg/kg p.o.) and other typical side effects were also observed after withdrawal of codeine. These results clearly demonstrate that flupirtine has no affinity for benzodiazepine receptors and is free of benzodiazepine or opiate/opioid-like abuse potential.
Nickel
B
B
Department of Pharmacology, ASTA Pharma AG, Frankfurt/Main, Fed. Rep. of Germany.
Borbe
H O
HO
Szelenyi
I
I
D000631:Aminopyridines / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D003975:Diazepam / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D008140:Lorazepam / Q000494:pharmacology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects; D012055:Reinforcement Schedule; D019966:Substance-Related Disorders / Q000523:psychology*
D000631:Aminopyridines; D000700:Analgesics; D014151:Anti-Anxiety Agents; D011963:Receptors, GABA-A; C034161:flupirtine; D008140:Lorazepam; D003975:Diazepam