New Li+-selective ionophores with the potential ability to mediate Li+-transport in vivo. Ionic selectivity and relative potencies, studied in model membranes.

A series of structurally-related Li+-selective ionophores were studied in planar lipid bilayer membranes, to assess their potential ability to act as Li+-selective carriers in vivo. The ionophores are acyclic, neutral molecules of similar structure: N,N'-diheptyl-N,N'-diR-5,5-dimethyl-3,7-dioxanonane diamide. The structural differences among them are the N-amide substituents (the R residues) as follows: an aliphatic ether (AS701), tetrahydrofuran (AS706), furan (AS708), an ester (AS702) and an amide (AS704). For each ionophore, the steady-state, single salt, membrane conductances and conductance-voltage behaviors were determined in the presence of LiCl, NaCl and MgCl2. Membrane zero-current potentials were measured for NaCl/LiCl and MgCl2/LiCl mixtures. All five ionophores were found to operate as "equilibrium-domain" carriers of monovalent ions. All select lithium over sodium, but with different magnitudes of selectivity, ranging from PLi/PNa of 13 (for AS701) to PLi/PNa of 2 (for AS708). The ionophores also differ in their ability to mediate Li+ membrane permeation, the order of decreasing potency being: AS701 greater than or equal to AS706 greater than AS702 greater than AS704 greater than or equal to AS708. Of the five molecules studied, the AS701 molecule was found to have the best Li+ over Na+ selectivity and highest potency. These findings indicate that this molecule has the best potential for mediating lithium-selective membrane permeation in vivo, among the group studied.