Hiroyoshi Hidaka,* Masaki Inagaki, Sachiyo Kawamoto, and Yasuharu Sasaki abstract: Naphthalenesulfonamides such as A-(6-amino-hexyl)-5-chloro-l-naphthalenesulfonamide (W-7) are potent calmodulin (CaM) antagonists and act upon several protein kinases at higher concentration. When the naphthalene ring was replaced by isoquinoline, the derivatives were no longer CaM antagonists but retained the ability to inhibit protein kinases, and some of the derivatives exhibited selective in-hibition toward a certain protein kinase. cAMP-dependent, cGMP-dependent, and Ca2+-phospholipid-dependent (protein kinase C) protein kinases were inhibited significantly by ad-dition of™ 6 A-[2-(methylamino) ethyl]-5-isoquinoline-sulfonamide (H-8) and l-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7). H-8 was the most active of the inhibitors in this series and inhibited more markedly cyclic nucleotide dependent protein kinases, than other kinases, while the derivative with the sulfonylpiperazine residue (H-7) was the most potent in inhibiting protein kinase C. Apparent K, values of H-8 were 0.48 and 1.2 µ for cGMP-dependentand cAMP-dependent protein kinases, respectively, and the K {value of H-7 for protein kinase C was 6 µ. Both the holoenzyme iRotein phosphorylation is an established major general mechanism by which intracellular events in mammalian tissues are controlled by external physiological stimuli (Rubin & Rosen, 1975; Krebs & Beavo, 1979; Krueger et al., 1977). Cyclic nucleotides, Ca2+-calmodulin (CaM), and diacylglycerol are universal regulators neither tissue nor species specific and have an effect on a large number of cellular functions (Greengard, 1978; Nishizuka, 1983). Biological functions of cyclic nucleotides, Ca2+-CaM, and diacylglycerol seem to be manifest through protein phosphorylations by cyclic nucleotides, Ca2+-CaM-dependent protein kinases, and protein kinase C. 1

Pharmacological studies using CaM antagonists such as phenothiazines and naphthalenesulfonamides suggest that Ca2+-CaM-dependent protein phosphorylation may play an important role in the function of various tissues including human platelets (Nishikawa et al., 1980) and tracheal smooth muscle contraction (Silver & Stull, 1983). On the other hand,