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A possible structural determinant of selectivity of boldine and derivatives for the α 1A ‐adrenoceptor subtype
Author(s) -
Madrero Y.,
Elorriaga M.,
Martinez S.,
Noguera M.A.,
Cassels B.K.,
D'Ocon P.,
Ivorra M.D.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb16073.x
Subject(s) - selectivity , chemistry , pharmacology , stereochemistry , biology , biochemistry , catalysis
1 The selectivity of action of boldine and the related aporphine alkaloids, predicentrine (9‐O‐methylboldine) and glaucine (2,9‐O‐dimethylboldine) on α 1 ‐adrenoceptor subtypes was studied by examining [ 3 H]‐prazosin competition binding in rat cerebral cortex. WB 4101 and benoxathian were used as selective α 1A ‐adrenoceptor antagonists. 2 In the competition experiments [ 3 H]‐prazosin (0.2 nM) binding was inhibited by WB 4101 and benoxathian. The inhibition curves displayed shallow slopes which could be subdivided into high and low affinity components (p K i = 9.92 and 8.29 for WB 4101, 9.35 and 7.94 for benoxathian). The two antagonists recognized approximately 37% of the sites with high affinity from among the total [ 3 H]‐prazosin specific binding sites. 3 Boldine, predicentrine and glaucine also competed for [ 3 H]‐prazosin (0.2 nM) binding with shallow and biphasic curves recognizing 30–40% of the sites with high affinity. Drug affinities (p K 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 α 1A ‐adrenoceptors was boldine (70 fold α 1A ‐selective) = predicentrine (60 fold, α 1A ‐selective) > glaucine (15 fold, α 1A ‐selective). 4 Pretreatment of rat cerebral cortex membranes with chloroethylclonidine (CEC, 10 μ m ) for 30 min at 37°C followed by thorough washing out reduced specific [ 3 H]‐prazosin binding by approximately 70%. The CEC‐insensitive [ 3 H]‐prazosin binding was inhibited by boldine monophasically (Hill slope = 0.93) with a single p K i value (7.76). 5 These results suggest that whereas the aporphine structure shared by these alkaloids is responsible for their selectivity of action for the a α 1A ‐adrenoceptor subtype in rat cerebral cortex, defined functional groups, namely the 2‐hydroxy function, induces a significant increase in α 1A ‐subtype selectivity and affinity.