Establishment of kappa opioid receptor agonists pharmacophore with molecular modeling method

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	Establishment of kappa opioid receptor agonists pharmacophore with molecular modeling method
	Liu, DX; Tang, Y; Jiang, HL; Chen, KX; Ji, RY
刊名	ACTA PHARMACOLOGICA SINICA
	1998-09
卷号	19 期号:5 页码:445-450
关键词	molecular mechanics kappa opioid receptors pharmacophore
ISSN号	0253-9756
文献子类	Article
英文摘要	AIM: To build up nonpeptide kappa-opioid receptor agonists pharmacophore. METHODS: Five structurally diverse, highly active nonpeptide kappa-opioid agonists were retrieved from MDL MDDR database. Molecular mechanics method were used to seek out 50 lower energy conformations for each compound. Taking nitrogen atom of pyrrolidine and acyl acetamide as overlay points, 5 agonists were superimposed to each other with their most favorite conformation. From the overlay map, the structure specificity of nonpeptide kappa-opioid receptor agonists were elucidated. RESULTS: According to pharmacophore, the pyrrolidine ring, carbonyl group of acyl acetamide, and the hydrophobic group attached to acyl acetamide were suggested to be the structure-specific moieties of kappa-opioid agonists. Moreover, by comparing kappa(1)-opioid receptor sequence of mouse with other G-protein-coupled receptors, we determined those conserve residues existing on transmembrane regions which might interact with the suggested groups. The carboxyl of Asp138 might interact with N atom of pyrrolidine by forming a hydrogen bond. The hydroxyl of Ser187 and the carbonyl group of kappa-opioid agonists might form another hydrogen bond, which was critical for its kappa selective affinity. The hydrophobic group attached to acyl acetamide might have hydrophobic interaction with aromatic residues of kappa-opioid receptors. CONCLUSION: These kappa agonists pharmacophore were helpful to select specific positions in the lead compounds to be occupied by hydrophobic moieties to limit their ability to across the blood-brain barrier.
WOS关键词	PROTEIN-COUPLED RECEPTORS ; BIOLOGICAL EVALUATION ; SIGMA-RECEPTOR ; ACETYLCHOLINE ; LIGANDS
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000075784800013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/274807]
专题	药物发现与设计中心药理学第三研究室
通讯作者	Chen, KX
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 200031, Peoples R China
推荐引用方式 GB/T 7714	Liu, DX,Tang, Y,Jiang, HL,et al. Establishment of kappa opioid receptor agonists pharmacophore with molecular modeling method[J]. ACTA PHARMACOLOGICA SINICA,1998,19(5):445-450.
APA	Liu, DX,Tang, Y,Jiang, HL,Chen, KX,&Ji, RY.(1998).Establishment of kappa opioid receptor agonists pharmacophore with molecular modeling method.ACTA PHARMACOLOGICA SINICA,19(5),445-450.
MLA	Liu, DX,et al."Establishment of kappa opioid receptor agonists pharmacophore with molecular modeling method".ACTA PHARMACOLOGICA SINICA 19.5(1998):445-450.