[Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes].
We examined the behavioral pharmacological properties of six benzodiazepine (omega) receptor ligands including brotizoram, nitrazepam, quazepam, rilmazafone, zolpidem and zopiclone and the binding of these drugs with omega receptor subtypes. Behavioral tests were performed at the time of the maximal effects induced by each drug following its oral administration to mice. All of these drugs dose-dependently induced impairment of motor coordination as rotarod performance and potentiation of thiopental-induced anesthesia as hypnotic effect. The hypnotic effects of rilmazafone, whose major metabolites were bound to both omega1 and omega2 receptors with high affinity, and omega1 selective quazepam were about 20 times more effective than the induction of motor impairments when compared with ED50 values. However, there was no difference between the ED50 values of omega1 selective zolpidem alone in these two tests. An antianxiety efficacy of zolpidem was relatively weak unlike that of other drugs in the elevated plus-maze. It has been reported that omega2, but not omega1, receptors are associated with motor impairment and anxiolytic effect. The weak anxiolytic effect of zolpidem supports the previous hypothesis. However, the strong motor incoordination of zolpidem suggests that not only omega2 but also omega1 receptors are related to motor impairment unlike the previous hypothesis.
Yasui
Mitsuru
M
Pharmaceutical Research & Development Division, Shionogi & Co., Ltd, Osaka, Japan. mituru.yasui@shionogi.co.jp
Kato
Akira
A
Kanemasa
Toshiyuki
T
Murata
Shunji
S
Nishitomi
Kohei
K
Koike
Katsumi
K
Tai
Nobuyuki
N
Shinohara
Shunji
S
Tokomura
Miwa
M
Horiuchi
Masahito
M
Abe
Kohji
K
D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism / Q000494:pharmacology*; D001569:Benzodiazepines / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006993:Hypnotics and Sedatives / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism / Q000502:physiology*; D013874:Thiopental / Q000494:pharmacology; D013997:Time Factors
D014151:Anti-Anxiety Agents; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D013874:Thiopental