New calcium indicators and buffers with high selectivity against magnesium and protons: design, synthesis, and properties of prototype structures

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Abstract
A new family of high-affinity buffers and optical indicators for Ca2+ is rationally designed and synthesized. The parent compound is 1,2-bis(o-aminophenoxy)ethane-N,N,N'',N''-tetraacetic acid (BAPTA), a relative of the chelator EGTA [ethylene glycol bis(.beta.-aminoethyl ether)-N,N,N'',N''-tetraacetic acid] in which methylene links between O2 and N are replaced by benzene rings. BAPTA and its derivatives share the high (> 105) selectivity for Ca2+ over Mg2+ of EGTA, but are very much less affected by pH changes and are faster at taking up and releasing Ca2+. The affinity of the parent compound for Ca2+ (Kd 1.1 .times. 10-7 M in 0.1 M KCl) may be strengthened or weakened by electron-releasing or -withdrawing substitutents on the aromatic rings. The Ca2+ and Mg2+ affinities may further be altered by replacing the ether oxygens by heterocyclic N atoms. The compounds described are fluorescent Ca2+ indicators absorbing in the UV region; the very large spectral shifts observed on binding Ca2+ fit the prediction that complexation should hinder the conjugation of the N lone-pair electrons with the aromatic rings. Derivatives with quinoline nuclei are notable for their high sensitivity of fluorescent quantum yield to the binding of Ca2+ but not of Mg2+. Preliminary biological tests have revealed little or no binding to membranes or toxic effects following intracellular microinjection.

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