| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2000: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1999: ¥1,800,000 (Direct Cost: ¥1,800,000)
|
|---|
| Research Abstract |
We have previously reported that dextromethorphan (DM), one of morphan derivatives, inhibited glycine-induced currents in single neuron acutely dissociated from rat brain. This study was designed to clarify the regulating site of glycine receptor function and to get further information about the action of DM and antitussives on other neuronal receptors and channels.
【Results】1) DM, strychnine, codeine and caffeine inhibited the glycine-induced cur-rents in Xenopus oocytes expressing α_1-or α_2a-subunit of glycine receptor. IC_<50S> for DM and codeine were 5.2x10^<-5>M and 2.2x10^<-4>M, respectively, in the α_1, and 1.2x10^<-5>M and 5.5x10^<-5> M, respectively in the α_2. Both drugs showed more potent inhibitory action on the α_2 than α_1, while the reverse was true for strychnine and caffeine. 2) Out of newly synthesized 11 compounds, which have a morphan structure in the molecule, three compounds inhibited the currents induced by glycine in Xenopus oocytes expressing the α_1 subunit. 3) In the mutants, Y161F, F159Y/Y161F and S267I, of the α_1, the inhibitory action of DM was not changed, compared with the action in the wild type. On the other hand, the action of strychnine was potentiated in the double mutant, F159Y/Y161F than in the wild type. 4) In patch-clamp study using acutely dissociated dorsal raphe neurons of rats, DM inhibited not only the K^+ currents induced by 5-HT with 1.43x10^<-5> M of the IC_<50>, but also the currents irreversibly activated by intracellular GTPγS even in the absence of 5-HT.The results sugest that (1) the morphan structure might be a part of chemical structure essential for modifing the function of glycine receptors, (2) DM may have a site on the glycine receptor different from the site where Str acts.
|
