title: Synthesis of mercapto-(+)-methamphetamine haptens and their use for obtaining improved epitope density on (+)-methamphetamine conjugate vaccines.
abstract: 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.
authors.affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709, USA. fic@rti.org
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Blough
authors.forename: Ramakrishna R
authors.initials: RR
authors.lastname: Pidaparthi
authors.forename: Philip
authors.initials: P
authors.lastname: Abraham
authors.forename: Paul K
authors.initials: PK
authors.lastname: Gong
authors.forename: Liu
authors.initials: L
authors.lastname: Deng
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Huang
authors.forename: Melinda
authors.initials: M
authors.lastname: Gunnell
authors.forename: Jackson O
authors.initials: JO
authors.lastname: Lay
authors.forename: Eric C
authors.initials: EC
authors.lastname: Peterson
authors.forename: S Michael
authors.initials: SM
authors.lastname: Owens
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology; D004337:Drug Carriers; D000939:Epitopes; D005260:Female; D006241:Haptens / Q000737:chemistry* / Q000276:immunology; D008301:Maleimides / Q000737:chemistry; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000737:chemistry; D012710:Serum Albumin, Bovine / Q000737:chemistry; D013237:Stereoisomerism; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000276:immunology; D014612:Vaccines / Q000138:chemical synthesis* / Q000276:immunology; D018074:Vaccines, Conjugate / Q000737:chemistry / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D004337:Drug Carriers; D000939:Epitopes; D006241:Haptens; D008301:Maleimides; D013438:Sulfhydryl Compounds; D014612:Vaccines; D018074:Vaccines, Conjugate; C043592:maleimide; D012710:Serum Albumin, Bovine; D008694:Methamphetamine; D010047:Ovalbumin