Development of peptidic dopamine transporter inhibitors via aromatic modification-mediated conformational restriction.
The dopamine transporter plays an important role in the molecular mechanism of cocaine dependence. It is suggested that inhibitors of the dopamine transporter would have strong therapeutic potential. Here we report that aromatic modification can constrain a linear peptide into the beta-turn conformation, which is preferred by the dopamine transporter. On the basis of this finding, a novel selective and competitive peptidic inhibitor of the dopamine transporter was developed. The peptide binds to the dopamine- and cocaine-binding site of the dopamine transporter and has behavioral effects different from those of cocaine in mice.
Ding
Jinguo
J
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, SIBS, Chinese Academy of Sciences, CAS, Shanghai, China.
Shi
Jiahao
J
Cui
Dafu
D
Xu
Linfeng
L
Duan
Shuhui
S
Guo
Lihe
L
Fei
Jian
J
D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D000697:Central Nervous System Stimulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003042:Cocaine / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017433:Protein Structure, Secondary; D011869:Radioligand Assay; D051381:Rats; D012201:Reward; D013329:Structure-Activity Relationship
D001565:Benzoates; D001713:Biphenyl Compounds; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D009281:Naphthalenes; D009842:Oligopeptides; D003042:Cocaine; D004298:Dopamine