Inhibition of eukaryote protein kinases by isoquinoline and oxazine alkaloids

The aporphine isoquinoline alkaloid apomorphine is a potent inhibitor of the catalytic subunit (cAK) of rat liver cyclic AMP-dependent protein kinase (PKA), myosin light chain kinase (MLCK), and Ca^2+- and phospholipid- dependent protein kinase C (PKC) (IC₅₀ values 1, 11, and 8 μM, respectively). However, a number of O-methylated analogues of apomorphine are inactive or poor inhibitors of cAK. The benzophenanthridine isoquinoline alkaloid sangulnarine is a potent inhibitor of cAK but is a relatively poor inhibitor of PKC (IC₅₀ values 6 and 217 μM respectively). However a number of methlylated analogues of sanguinarine are inactive as cAK inhibitors. The aporphine isoquinoline alkaloids (+)-boldine and bulbocapnine are non- competitive inhibitors of MLCK with respect to both peptide substrate and ATP. The inhibition of cAK, MLCK, and PKC by apomorphine and sanguinarin is competitive with respect to ATP as substrate. The oxazine alkaloids darrow red, nile blue A, and oxazine 170 are variously effective as inhibitors of cAK, MLCK, PKC, and CDPK (IC ₅₀ value 4-65 μM). Ca²⁺ binds of apomorphine and (+)-boldine which, together with nile blue A and oxazine 170, are potent inhibitors of calmodulin (CaM)-dependent MLCK (IC₅₀ values 11, 4, and 7 μM, respectively), and interact with dansyl-CaM.