Synthesis of Mercapto-(+)-methamphetamine Haptens and Their Use for Obtaining Improved Epitope Density on (+)-Methamphetamine Conjugate Vaccines
by Carroll, F. I.; Blough, B. E.; Pidaparthi, R. R.; Abraham, P.; Gong, P. K.; Deng, L.; Huang, X. D.; Gunnell, M.; Lay, J. O.; Peterson, E. C.; Owens, S. M.
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.
- Journal
- Journal of Medicinal Chemistry
- Volume
- 54
- Issue
- 14
- Year
- 2011
- Start Page
- 5221-5228
- URL
- https://dx.doi.org/10.1021/jm2004943
- ISBN/ISSN
- 1520-4804; 0022-2623
- DOI
- 10.1021/jm2004943