HMN-709, a Chlorobenzenesulfonamide Derivative, Is a New Membrane-Permeable Calmodulin Antagonist

[摘要] References(47)Cited-By(1)Our objective is to describe the basic chemical and biological properties of the new calmodulin antagonist HMN-709 (2-[N-(2-aminoethyl)-N-(4-chlorobenzenesulfonyl)]amino-N-(4-fluorocinnamyl)-N-methylbenzylamine). This newly synthesized compound was found to inhibit the Ca2+/calmodulin-dependent activation of calmodulin kinase I, smooth muscle myosin light chain kinase and Ca2+-phosphodiesterase with IC50 Values of 1.57±0.21, 2.29±0.09 and 0.30±0.08 μM (mean±S.E.), respectively. This compound showed little or no effect on the Ca2+/calmodulin-independent activation of protein kinase A, protein kinase C and basal phosphodiesterase. In addition, HMN-709 inhibited calmodulin kinase I competitively with respect to calmodulin (Ki=0.88 μM) and non-competitively with respect to ATP. Affinity chromatography, with HMN-709-coupled Sepharose HP, showed that the compound bound to calmodulin in a Ca2+-dependent manner and did not bind to calmodulin kinase I. These results suggest that HMN-709 antagonizes calmodulin by binding to Ca2+/calmodulin. HMN-709 inhibited collagen-induced platelet aggregation with an IC50 value of 11.80±0.86 μM (mean±S.E.) without inhibiting phorbol 12, 13-dibutyrate-induced aggregation at doses up to 12 μM. HMN-709 appears to be a new, membrane-permeable calmodulin antagonist that may be used for studying the involvement of calmodulin in cellular processes.

[学科分类] 药理学

[关键词] Calmodulin;Calmodulin antagonist;IC50;Affinity chromatography;Platelet function