Molecular Pharmacology, Vol 20, 571-578, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Activity-Structure Relationship of Calmodulin Antagonists

Naphthalenesulfonamide Derivatives

¹ Department of Pharmacology, Mie University School of Medicine, Edobashi, Tsu 514, Japan

The role of calmodulin in vascular response was investigated using two series of synthesized naphthalenesulfonamide derivatives. The actions of these compounds as calmodulin antagonists and vascular relaxants were shown to depend both on the chlorination of the naphthalene ring and on the length of the alkyl chain (C₅-C₁₀). A good correlation between potency in relaxation of these strips and affinity to calmodulin was obtained, thereby indicating that the mechanism of relaxation of these compounds is probably due to their effects on the Ca²⁺-calmodulin-dependent process. N-(6-Aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) produced relaxation of contracted vascular strips with various contractile agonists, whereas this derivative contracted the strip in the absence of contractile agonists, suggesting that this contractile response produced by W-7 is masked in the presence of a contractile agonist. To clarify the mechanism of W-7-elicited contraction of vascular strips in the absence of contractile agonists, the effect of W-7 was examined on the spontaneous efflux of [³H]norepinephrine ([³H]NE) which had been preloaded to the strip; W-7 was compared with N-(6-aminohexyl)-1-naphthalenesulfonamide (W-5), a chlorine-deficient derivative of W-7 which has a lower affinity for calmodulin than does W-7. Both W-7- and W-5-induced contractions were associated with increases in the [³H]NE efflux and were inhibited by the addition of an alpha-adrenergic blocker, phentolamine. Other chlorine-deficient derivatives of W-7 which also had lower affinities for calmodulin increased the [³H]NE efflux with vascular strip contraction, suggesting no correlation between the potency in increasing the [³H]NE efflux and the affinity to calmodulin. Chlorine-deficient derivatives such as W-5 produced contraction in both the presence and absence of contractile agonists which were inhibited by phentolamine. Although W-7-induced relaxation of vascular strips was produced in the presence of Ca²⁺, the increase in [³H]NE efflux by W-7 and its derivatives was independent of Ca²⁺, suggesting that this increase in the [³H]NE efflux is not related to the Ca²⁺-calmodulin system. Thereby, W-7, a calmodulin antagonist, has at least two kinds of pharmacological actions: one is calmodulin-related relaxation and another is calmodulin-independent contraction. These chlorine-deficient derivatives seems to serve as so-called control agents of the calmodulin antagonist W-7, and these pairs of structually related naphthalenesulfonamides are useful tools with which to elucidate the function of calmodulin.

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ACKNOWLEDGMENT We thank M. Ohara, Kyushu University, for critical reading of the manuscript.

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