ABSTRACT
The aim of the present study was to synthesise and screen a set of novel nicotine hapten immunogens used for the treatment of nicotine dependence. In the screening process we studied the amount of antibodies generated and their selectivity, using ELISA techniques, and their effects on nicotine-induced dopamine release in the NAC(shell) of the rat, assessed by in vivo voltammetry. We conclude that even small changes such as the linker attachment on the nicotine molecule as well as the structure of the linker may greatly influence the selectivity of the antibodies and the central neurobiological effects of nicotine that are considered critical for its dependence producing properties.
Subject(s)
Drug Evaluation, Preclinical/methods , Haptens/immunology , Nicotine/immunology , Substance-Related Disorders/therapy , Vaccines/therapeutic use , Animals , Antibodies/blood , Dopamine/metabolism , Enzyme-Linked Immunosorbent Assay , Haptens/chemistry , Male , Molecular Structure , Nicotine/chemistry , Rats , Rats, WistarABSTRACT
We disclose an efficient procedure for the preparation of ethers of 2-substituted 2-hydroxymethylpyrroline and of 2-aminomethyl-3-pyrrolines, involving, as a key step, formation and nucleophilic ring opening of a cyclic sulfamidate. Several new analogs of epibatidine (1) and tebanicline (ABT-594, 2) were prepared and tested for analgesic activity in the mouse formalin model.
Subject(s)
Analgesics, Non-Narcotic/chemistry , Analgesics, Non-Narcotic/pharmacology , Azetidines/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Pyridines/chemistry , Analgesics, Non-Narcotic/chemical synthesis , Animals , Azetidines/chemical synthesis , Azetidines/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Mice , Models, Chemical , Molecular Structure , Pain/drug therapy , Pyridines/chemical synthesis , Pyridines/pharmacologyABSTRACT
The reactions of alpha,beta-unsaturated amide/triflic anhydride complexes (generated in situ from the corresponding amides and triflic anhydride) with dithiophenes and dithienylmethanes proceed as tandem alkylation-Vilsmeier-Haack acylation to form dithieno- and dibenzothieno-fused cycloheptanones and cyclooctanones in moderate to good yields. The reactions of 2-bromo-N,N-dimethylacrylamide/triflic anhydride complex allow preparation of tropones in a simple one-pot procedure. The reaction of 2,2-dibenzothienylmethane with dimethylacrylamide/triflic anhydride complex proceeds unusually to afford dimethylaminonaphthalene in addition to the predictable fused cyclooctanone.
