心理藥物的新街邊仔
Photograph courtesy of Sharon Freeman (Merck Sharp and Dohme Laboratories).
只有少數(shù)心理藥物能夠超越化學(xué)的秘方而擁有大眾化的名字。Valium(diazepam)就是其中歷久彌新的藥物之一。盡管diazepam的副作用如遺忘癥、鎮(zhèn)靜、運(yùn)動共濟(jì)失調(diào)等眾人皆知,但它還是治療焦慮癥的主要選擇。在Nature
Neuroscience上, McKernan etal.開發(fā)出一個與diazepam幾乎同樣療效但副作用少得多的新藥物。
Diazepam作用機(jī)理是使通過GABAA受體的電流增加。GABAA受體為五聚體,有超過15個不同的亞基,diazepam作用在此受體上,其特異性是如何表現(xiàn)的呢?
Rudolph etal.在Nature上報(bào)道,突變了α1亞基的小鼠由diazepam引起的鎮(zhèn)靜副作用下降,但抗焦慮功效不受影響。McKernan etal.的進(jìn)一步研究確證了此突變體小鼠由diazepam引起的運(yùn)動共濟(jì)失調(diào)癥狀也有所減輕。他們由此開發(fā)出一種新藥L-838,417,它作用在GABAA的一系列受體上都可表現(xiàn)出與diazepam類似的活性,唯獨(dú)對包括α1亞基的五聚體受體沒有作用。當(dāng)L-838,417對野生型小鼠給藥時,能夠減輕焦慮癥狀,卻沒有運(yùn)動共濟(jì)失調(diào)和鎮(zhèn)靜等副作用。
, 百拇醫(yī)藥
雖然對小鼠焦慮的行為學(xué)測試是否能真實(shí)的量度人類焦慮的問題尚有疑問,但可以肯定的是L-838,417確實(shí)是針對焦慮狀態(tài)一個神奇的藥物,而且,Rudolph etal.和McKernan etal.的這項(xiàng)研究讓我們看到了將分子遺傳學(xué)手段與醫(yī)藥化學(xué)手段聯(lián)合起來對臨床藥物的開發(fā)所能起到的巨大推動力。
The elevated plus maze, a commonly used animal model of anxiety. The experimenter places the mouse on the central platform and measures the time it spends in the open arms. Anxiolytics increase
this time as well as the number of occasions the mouse ventures into
, 百拇醫(yī)藥
the open. Photograph courtesy of Roy Hammans (Merck Sharp and Dohme Laboratories).
相關(guān)文章:
Original research papers
McKernan et al. Sedative but not anxiolytic properties
of benzodiazepines are mediated by the GABAA receptor a1 subtype. Nat.
Neurosci. 3, 587–592 (2000).
Rudolph et al. Benzodiazepine actions mediated by
, 百拇醫(yī)藥
specific g-aminobutyric acidA receptor subtypes. Nature 401, 796-800 (1999).
News and Views tecott, L. H. Designer genes and anti-anxiety drugs.
Nat. Neurosci. 3, 529–530 (2000).
Wisden, W. & Stephens, D. N. Towards better
benzodiazepines. Nature 401, 751-752 (1999). REVIEWS
Barnard, E. A. et al. International Union of Pharmacology. XV. Subtypes of g-aminobutyric acid A receptors:
, 百拇醫(yī)藥
classification on the basis of subunit structure and receptor
function. Pharmacol. Rev. 50, 291–313 (1998).
Costa, E. From GABAA receptor diversity emerges a
unified vision of GABAergic inhibition. Annu. Rev. Pharmacol. Toxicol.
38, 321-350 (1998)
新思路
新技術(shù)—其他文章, 百拇醫(yī)藥
只有少數(shù)心理藥物能夠超越化學(xué)的秘方而擁有大眾化的名字。Valium(diazepam)就是其中歷久彌新的藥物之一。盡管diazepam的副作用如遺忘癥、鎮(zhèn)靜、運(yùn)動共濟(jì)失調(diào)等眾人皆知,但它還是治療焦慮癥的主要選擇。在Nature
Neuroscience上, McKernan etal.開發(fā)出一個與diazepam幾乎同樣療效但副作用少得多的新藥物。
Diazepam作用機(jī)理是使通過GABAA受體的電流增加。GABAA受體為五聚體,有超過15個不同的亞基,diazepam作用在此受體上,其特異性是如何表現(xiàn)的呢?
Rudolph etal.在Nature上報(bào)道,突變了α1亞基的小鼠由diazepam引起的鎮(zhèn)靜副作用下降,但抗焦慮功效不受影響。McKernan etal.的進(jìn)一步研究確證了此突變體小鼠由diazepam引起的運(yùn)動共濟(jì)失調(diào)癥狀也有所減輕。他們由此開發(fā)出一種新藥L-838,417,它作用在GABAA的一系列受體上都可表現(xiàn)出與diazepam類似的活性,唯獨(dú)對包括α1亞基的五聚體受體沒有作用。當(dāng)L-838,417對野生型小鼠給藥時,能夠減輕焦慮癥狀,卻沒有運(yùn)動共濟(jì)失調(diào)和鎮(zhèn)靜等副作用。
, 百拇醫(yī)藥
雖然對小鼠焦慮的行為學(xué)測試是否能真實(shí)的量度人類焦慮的問題尚有疑問,但可以肯定的是L-838,417確實(shí)是針對焦慮狀態(tài)一個神奇的藥物,而且,Rudolph etal.和McKernan etal.的這項(xiàng)研究讓我們看到了將分子遺傳學(xué)手段與醫(yī)藥化學(xué)手段聯(lián)合起來對臨床藥物的開發(fā)所能起到的巨大推動力。
The elevated plus maze, a commonly used animal model of anxiety. The experimenter places the mouse on the central platform and measures the time it spends in the open arms. Anxiolytics increase
this time as well as the number of occasions the mouse ventures into
, 百拇醫(yī)藥
the open. Photograph courtesy of Roy Hammans (Merck Sharp and Dohme Laboratories).
相關(guān)文章:
Original research papers
McKernan et al. Sedative but not anxiolytic properties
of benzodiazepines are mediated by the GABAA receptor a1 subtype. Nat.
Neurosci. 3, 587–592 (2000).
Rudolph et al. Benzodiazepine actions mediated by
, 百拇醫(yī)藥
specific g-aminobutyric acidA receptor subtypes. Nature 401, 796-800 (1999).
News and Views tecott, L. H. Designer genes and anti-anxiety drugs.
Nat. Neurosci. 3, 529–530 (2000).
Wisden, W. & Stephens, D. N. Towards better
benzodiazepines. Nature 401, 751-752 (1999). REVIEWS
Barnard, E. A. et al. International Union of Pharmacology. XV. Subtypes of g-aminobutyric acid A receptors:
, 百拇醫(yī)藥
classification on the basis of subunit structure and receptor
function. Pharmacol. Rev. 50, 291–313 (1998).
Costa, E. From GABAA receptor diversity emerges a
unified vision of GABAergic inhibition. Annu. Rev. Pharmacol. Toxicol.
38, 321-350 (1998)
新思路
新技術(shù)—其他文章, 百拇醫(yī)藥
百拇醫(yī)藥網(wǎng) http://www.www.srpcoatings.com/Html/Info/News/66/06691.htm