Halogenated derivatives of boldine with high selectivity for α1A-adrenoceptors in rat cerebral cortex

The selectivity of 3-nitrosoboldine and different halogenated derivatives of boldine (3-bromoboldine, 3,8-dibromoboldine and 3-chloroboldine) for alpha(1)-adrenoceptor subtypes was studied by examining [H-3]-prazosin competition binding in rat cerebral cortex. In the competition experiments [H-3]-prazosin binding was inhibited completely by all the compounds tested. The inhibition curves displayed shallow slopes which could be subdivided into high and low affinity components. The relative order of affinity and selectivity for alpha(1A)-adrenoceptors was 3-bromoboldine = 3,8-dibromoboldine = 3-chloroboldine > boldine > 3-nitrosoboldine. The competition curves for 3-bromoboldine remained shallow and biphasic following chloroethylclonidine treatment. Whereas the relative contribution of the high affinity sites increased, the 3-bromoboldine affinities at its high and low affinity sites remained similar to those obtained in untreated membranes. 3-Bromoboldine, 3,8-dibromoboldine, 3-chloroboldine and 3-nitrosoboldine did not significantly displace [H-3]-(+)-cis-diltiazem binding to rat cerebral cortex membranes. This activity was lower than that shown by boldine. Compared to boldine, halogen (bromine or chlorine) substitution at position 3 increases the alpha(1A)-adrenoceptor subtype selectivity and decreases the affinity for the benzothiazepine binding site at the calcium channel. Further halogen substitution at position 8 did not significantly improve this activity with respect to 3-bromoboldine. in contrast, the NO substitution at position 3 of boldine (3-nitrosoboldine) gives a loss of affinity and selectivity for alpha(1)-adrenoceptor subtypes.