Discovery, Synthesis, and Structure Activity of a Highly Selective 7 Nicotinic Acetylcholine Receptor Antagonist
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- 作者：Paul Whiteaker ; Sean Christensen ; Doju Yoshikami ; Cheryl Dowell ; Maren Watkins ; Jozsef Gulyas ; Jean Rivier ; Baldomero M. Olivera ; J. Michael McIntosh
- 刊名：Biochemistry
- 出版年：2007
- 出版时间：June 5, 2007
- 年：2007
- 卷：46
- 期：22
- 页码：6628 - 6638
- 全文大小：133K
- 年卷期：v.46,no.22(June 5, 2007)
- ISSN：1520-4995
文摘
Nicotinic acetylcholine receptors (nAChRs) that contain an 
7 subunit are widely distributedin neuronal and nonneuronal tissue. These receptors are implicated in the release of neurotransmitterssuch as glutamate and in functions ranging from thought processing to inflammation. Currently availableligands for 7 nAChRs have substantial affinity for one or more other nAChR subtypes, including thosewith an 1, 3, 6, and/or 9 subunit. An -conotoxin gene was cloned from Conus arenatus. Predictedpeptides were synthesized and found to potently block 3-, 6-, and 7-containing nAChRs. Structure-activity information regarding conotoxins from distantly related Conus species was employed to modifythe C. arenatus derived toxin into a novel, highly selective 7 nAChR antagonist. This ligand, -CtxArIB[V11L,V16D], has low nanomolar affinity for rat 7 homomers expressed in Xenopus laevis oocytes,and antagonism is slowly reversible. Kinetic analysis provided insight into the mechanism of antagonism.-CtxArIB interacts with five ligand binding sites per 7 receptor, and occupation of a single site issufficient to block function. The peptide was also shown to be highly selective in competition bindingassays in rat brain membranes. -CtxArIB[V11L,V16D] is the most selective ligand yet reported for 7nAChRs.
7 subunit are widely distributedin neuronal and nonneuronal tissue. These receptors are implicated in the release of neurotransmitterssuch as glutamate and in functions ranging from thought processing to inflammation. Currently availableligands for 7 nAChRs have substantial affinity for one or more other nAChR subtypes, including thosewith an 1, 3, 6, and/or 9 subunit. An -conotoxin gene was cloned from Conus arenatus. Predictedpeptides were synthesized and found to potently block 3-, 6-, and 7-containing nAChRs. Structure-activity information regarding conotoxins from distantly related Conus species was employed to modifythe C. arenatus derived toxin into a novel, highly selective 7 nAChR antagonist. This ligand, -CtxArIB[V11L,V16D], has low nanomolar affinity for rat 7 homomers expressed in Xenopus laevis oocytes,and antagonism is slowly reversible. Kinetic analysis provided insight into the mechanism of antagonism.-CtxArIB interacts with five ligand binding sites per 7 receptor, and occupation of a single site issufficient to block function. The peptide was also shown to be highly selective in competition bindingassays in rat brain membranes. -CtxArIB[V11L,V16D] is the most selective ligand yet reported for 7nAChRs.