一項研究說,，科學家在設計針對大腦尼古丁成癮受體的戒煙藥物方面可能得到更好的手段,。尼古丁與神經(jīng)受體結合并激活讓信號傳遞到神經(jīng)元的通道，但是人們只是部分理解了這一結合過程,。為了審視這種結合的一個關鍵相互作用,，Dennis Dougherty及其同事根據(jù)與尼古丁結合但是不參與大腦功能的蛋白質的結構合成了氨基酸和藥物類似物。
這組作者說,，這種試驗性的技術揭示出了這種藥物和一種受體的特定亞單位的一個關鍵氫鍵,，這種受體與尼古丁成癮有很強的相關性。這組作者說,，這種氫鍵的發(fā)現(xiàn)確立了關于尼古丁如何觸發(fā)大腦信號的一個完整的概念模型,。這組作者說，科學家可以使用這個稱為“藥效團“的模型作為設計執(zhí)行與尼古丁相同的活動但是產(chǎn)生不同結果的藥物的一個模板,。（生物谷www.bioon.net）
生物谷推薦原文出處：
PNAS doi: 10.1073/pnas.1007140107
Nicotinic pharmacophore: The pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH
Angela P. Blum a, Henry A. Lester b, and Dennis A. Dougherty a,1
aDivision of Chemistry and Chemical Engineering; and
bDivision of Biology, California Institute of Technology, Pasadena, CA 91125
Pharmacophore models for nicotinic agonists have been proposed for four decades. Central to these models is the presence of a cationic nitrogen and a hydrogen bond acceptor. It is now well-established that the cationic center makes an important cation-π interaction to a conserved tryptophan, but the donor to the proposed hydrogen bond acceptor has been more challenging to identify. A structure of nicotine bound to the acetylcholine binding protein predicted that the binding partner of the pharmacophore’s second component was a water molecule, which also hydrogen bonds to the backbone of the complementary subunit of the receptors. Here we use unnatural amino acid mutagenesis coupled with agonist analogs to examine whether such a hydrogen bond is functionally significant in the α4β2 neuronal nAChR, the receptor most associated with nicotine addiction. We find evidence for the hydrogen bond with the agonists nicotine, acetylcholine, carbamylcholine, and epibatidine. These data represent a completed nicotinic pharmacophore and offer insight into the design of new therapeutic agents that selectively target these receptors.
