? This proposal systematically probes the immune response for catalytic antibodies to degrade flunitrazepam, an abused benzodiazepine also implicated in drug-assisted sexual and/or physical assault. Flunitrazepam is a central nervous system depressant with prolonged sedative-hypnotic effects that also induces anterograde amnesia. Three different flunitrazepam analog haptens are designed to exploit the known degradation pathways of the drug using established methods to generate catalytic antibodies. Two haptens are constructed in a transition-state analog approach, targeting 1,2-amide hydrolysis of flunitrazepam, replacing the amide with a phosphonamidate in one hapten and a sulfonamide in the other. A third hapten targets the 4,5-imine of flunitrazepam, replacing it with a proximal carboxylate that is negatively charged at physiological pH. During immunization this hapten will program a positive point charge in the antibody to initiate imine hydrolysis when flunitrazepam is given as a substrate. Hybridoma technology is used to generate monoclonal antibodies for all three haptens. Catalysis will be analyzed using the intrinsic chromophores of flunitrazepam and its degradation products. Active and passive immunizations possess therapeutic utility. ? ? ?
| Brogan, Andrew P; Dickerson, Tobin J; Janda, Kim D (2007) Nornicotine-organocatalyzed aqueous reduction of alpha,beta-unsaturated aldehydes. Chem Commun (Camb) :4952-4 |
| Brogan, Andrew P; Eubanks, Lisa M; Koob, George F et al. (2007) Antibody-catalyzed oxidation of delta(9)-tetrahydrocannabinol. J Am Chem Soc 129:3698-702 |
