A POSSIBLE STRUCTURAL DETERMINANT OF SELECTIVITY OF BOLDINE AND DERIVATIVES FOR THE ALPHA(1A)-ADRENOCEPTOR SUBTYPE

1 The selectivity of action of boldine and the related aporphine alkal oids, predicentrine (9-O-methylboldine) and glaucine (2,9-O-dimethylbo ldine) on alpha(1)-adrenoceptor subtypes was studied by examining [H-3 ]-prazosin competition binding in rat cerebral cortex. WB 4101 and ben oxathian were used as selective alpha(1A)-adrenoceptor antagonists. 2 In the competition experiments [H-3]-prazosin (0.2 nM) binding was inh ibited by WE 4101 and benoxathian. The inhibition curves displayed sha llow slopes which could be subdivided into high and low affinity compo nents (pK(i)=9.92 and 8.29 for WE 4101, 9.35 and 7.94 for benoxathian) . The two antagonists recognized approximately 37% of the sites with h igh affinity from among the total [H-3]-prazosin specific binding site s. 3 Boldine, predicentrine and glaucine also competed for [3H]-prazos in (0.2 nM) binding with shallow and biphasic curves recognizing 30-40 % of the sites with high affinity. Drug affinities (pK(i)) at the high and low affinity sites were, 8.31 and 6.50, respectively, for boldine , 8.13 and 6.39 for predicentrine, and 7.12 and 5.92 for glaucine. The relative order of selectivity for alpha(1A)-adrenoceptors was boldine (70 fold alpha(1A)-selective)=predicentrine (60 fold, alpha(1A)-selec tive)> glaucine (15 fold, alpha(1A)-selective). 4 Pretreatment of rat cerebral cortex membranes with chloroethylclonidine (CEC, 10 mu M) for 30 min at 37 degrees C followed by thorough washing out reduced speci fic [H-3]-prazosin binding by approximately 70%. The CEC-insensitive [ H-3]-prazosin binding was inhibited by boldine monophasically (Hill sl ope=0.93) with a single pK(i) value (7.76). 5 These results suggest th at whereas the aporphine structure shared by these alkaloids is respon sible for their selectivity of action for the alpha(1A)-adrenoceptor s ubtype in rat cerebral cortex, defined functional groups, namely the 2 -hydroxy function, induces a significant increase in alpha(1A)-subtype selectivity and affinity.