Synthesis of Mercapto-(+)-methamphetamine Haptens and Their Use for Obtaining Improved Epitope Density on (+)-Methamphetamine Conjugate Vaccines

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• 作者：F. Ivy Carroll ; Bruce E. Blough ; Ramakrishna R. Pidaparthi ; Philip Abraham ; Paul K. Gong ; Liu Deng ; Xiaodong Huang ; Melinda Gunnell ; Jackson O. Lay ; Jr. ; Eric C. Peterson ; S. Michael Owens
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 28, 2011
• 年：2011
• 卷：54
• 期：14
• 页码：5221-5228
• 全文大小：838K
• 年卷期：v.54,no.14(July 28, 2011)
• ISSN：1520-4804

文摘

This study reports the synthesis of the mercapto-hapten (S)-N-(2-(mercaptoethyl)-6-(3-(2-(methylamino)propyl)phenoxy)hexanamide [3, (+)-METH HSMO9] and its use to prepare METH-conjugated vaccines (MCV) from maleimide-activated proteins. MALDI-TOF mass spectrometry analysis of the MCV synthesized using 3 showed there was a high and controllable epitope density on two different carrier proteins. In addition, the MCV produced a substantially greater immunological response in mice than previous METH haptens, and a monoclonal antibody generated from this MCV in mice showed a very high affinity for (+)-METH (K_D = 6.8 nM). The efficient covalent coupling of (+)-METH HSMO9 to the activated carrier proteins suggests that this approach could be cost-effective for large-scale production of MCV. In addition, the general methods described for the synthesis of (+)-METH HSMO9 (3) and its use to synthesize MCV will be applicable for conjugated vaccines of small molecules and other substances of abuse such as morphine, nicotine, and cocaine.