Halogenated boldine derivatives with enhanced monoamine receptor selectivity

(S)-(+)-Boldine (1) was brominated, chlorinated, and iodinated using molecu lar bromine in acetic acid or N-halosuccinimides in trifluoroacetic acid. I nitial halogenation occurs at C-3, followed (in the cases of chlorine and b romine) by the less reactive C-8, to afford 3-haloboldines- and 3,8-dihalob oldines (2-5). Using a 2:1 ratio of N-iodosuccinimide to boldine, however, only the 3-iodo derivative 6 was obtained. Radioligand binding studies of t hese products showed that halogenation of boldine at C-3 favors affinity fo r D-1-(vs D-2-) dopaminergic receptors, attaining a low nanomolar IC50 valu e in the case of 3-iodoboldine (6).