Opioid peptide receptor studies, 11: Involvement of Tyr148, Trp318 and His319 of the rat mu-opioid receptor in binding of mu-selective ligands

doi:10.1002/(SICI)1098-2396(199904)32:1<23::AID-SYN3>3.0.CO;2-N

	Opioid peptide receptor studies, 11: Involvement of Tyr148, Trp318 and His319 of the rat mu-opioid receptor in binding of mu-selective ligands
	Xu, H ; Lu, YF ; Partilla, JS ; Zheng, QX ; Wang, JB ; Brine, GA ; Carroll, FI ; Rice, KC ; Chen, KX; Chi, ZQ
刊名	SYNAPSE
	1999-04
卷号	32 期号:1 页码:23-28
关键词	opioid receptors ligand binding fentanyl molecular modeling mutagenesis
ISSN号	0887-4476
DOI	10.1002/(SICI)1098-2396(199904)32:1<23::AID-SYN3>3.0.CO;2-N
文献子类	Article
英文摘要	Previous data obtained with the cloned rat mu opioid receptor demonstrated that the "super-potent" opiates, ohmefentanyl (RTI-4614-4) and its four enantiomers, differ in binding affinity, potency, efficacy, and intrinsic efficacy. Molecular modeling (Tang et al., 1996) of fentanyl derivatives binding to the mu receptor suggests that Asp147, Tyr148, Trp318, and His319 are important residues for binding. According to this model, Asp147 interacts with the positively charged opiate agonist to form potent electrostatic and hydrogen-bonding interactions. In this study, the role of weak electrostatic and hydrogen-bonding "pi-pi" interactions of the O atom of the carbonyl group and the phenyl ring structures of RTI-4614-4 and its four enantiomers with residues Tyr148, Trp318, and His319 were explored via site-directed mutagenesis. Tyr148 tin transmembrane helix 3 {TMH3}), Trp318 (TMH7), and His319 (TMH7) were individually replaced with phenylalanine or alanine. Receptors transiently expressed in COS-7 cells were labeled with [I-125]IOXY according to published procedures. Mutation of Tyr148 to phenylalanine reduced the binding affinities of some mu-selective agonists (2-7 fold) but did not alter the affinities of DAMGO, naloxone, and the non-selective opiates etorphine and buprenorphine. In contrast, this mutation significantly increased the binding affinities (decreased the Kd values) of [D-Al(a)2,D-Leu(5)]enkephalin, IOXY, and dermorphin. Mutation of Trp318 decreased opioid receptor binding to almost undetectable levels. Substitution of alanine for His319 significantly reduced binding affinities for the opioid ligands tested (1.3- to 48-fold), but did not alter the affinities of naloxone and bremazocine. These results indicate the importance of Tyr148 and His319 for the binding of fentanyl derivatives to the mu receptor. Functional studies using the mutant receptors will provide additional insight into the mechanism of action of RTI-4614-4 and its four enantiomers. Synapse 32:23-28, 1999, Published 1999 Wiley-Liss, Inc.
WOS关键词	OPIATE RECEPTOR ; BRAIN
WOS研究方向	Neurosciences & Neurology
语种	英语
出版者	WILEY
WOS记录号	WOS:000078855700003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/274742]
专题	中国科学院上海药物研究所
通讯作者	Rothman, RB
作者单位	1.Res Triangle Inst, Res Triangle Pk, NC 27709 USA 2.NIDDK, Med Chem Lab, NIH, Bethesda, MD 20892 USA 3.NIDA, Clin Psychopharmacol Sect, Div Intramural Res, NIH, Baltimore, MD 21224 USA 4.UMAB, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA 5.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 200031, Peoples R China
推荐引用方式 GB/T 7714	Xu, H,Lu, YF,Partilla, JS,et al. Opioid peptide receptor studies, 11: Involvement of Tyr148, Trp318 and His319 of the rat mu-opioid receptor in binding of mu-selective ligands[J]. SYNAPSE,1999,32(1):23-28.
APA	Xu, H.,Lu, YF.,Partilla, JS.,Zheng, QX.,Wang, JB.,...&Rothman, RB.(1999).Opioid peptide receptor studies, 11: Involvement of Tyr148, Trp318 and His319 of the rat mu-opioid receptor in binding of mu-selective ligands.SYNAPSE,32(1),23-28.
MLA	Xu, H,et al."Opioid peptide receptor studies, 11: Involvement of Tyr148, Trp318 and His319 of the rat mu-opioid receptor in binding of mu-selective ligands".SYNAPSE 32.1(1999):23-28.