Selective inhibition of catalytic activity of smooth muscle myosin light chain kinase.
Systematically synthesized derivatives of ML-9, 1-(5-chloronaphthalenesulfonyl)-1H-hexahydro-1,4-diazepine, were found to inhibit both Ca2+-calmodulin-dependent and -independent smooth muscle myosin light chain kinases with a similar concentration dependence, and their inhibitions were of the competitive type with respect to ATP. Moreover, ML-9 as well as ATP or ADP exhibited an effective protection to inactivation of smooth muscle myosin light chain kinase by the nucleotide affinity label 5'-p-fluorosulfonylbenzoyladenosine, suggesting that ML-9 binds at or near the ATP-binding site on the kinase molecule. These derivatives, which were structurally unrelated to ATP and exhibited more hydrophobic properties detected by reverse-phase high-performance liquid chromatography, exhibited more potent inhibition toward smooth muscle myosin light chain kinase, indicating that the hydrophobic properties of these derivatives positively correlated well with their potencies of inhibiting the catalytic activity for the enzyme. These findings suggest that the ATP-binding site at the active center of smooth muscle myosin light chain kinase is located in a hydrophobic environment. The potent vaso-relaxing effect of ML-9 on rabbit vascular strips and on saponin-treated skinned smooth muscle cells was discussed in relation to the in vivo inhibition by this drug of smooth muscle myosin light chain kinase.
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001792:Blood Platelets / Q000201:enzymology; D002118:Calcium / Q000494:pharmacology; D002645:Chickens; D004533:Egtazic Acid / Q000494:pharmacology; D005895:Gizzard, Avian / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D009130:Muscle, Smooth / Q000201:enzymology*; D009132:Muscles / Q000201:enzymology; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors*; D009282:Naphthalenesulfonates / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism
D001381:Azepines; D009282:Naphthalenesulfonates; D004533:Egtazic Acid; C010959:5'-(4-fluorosulfonylbenzoyl)adenosine; D011494:Protein Kinases; D009219:Myosin-Light-Chain Kinase; D000241:Adenosine; D002118:Calcium