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 (AS 701), tetrahydrofuran (AS 706), furan (AS 708), an ester (AS 702) and an amide (AS 704) 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 measurd 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 P_Li/P_Na of 13 (for AS 701) to P_Li/P_Na of 2 (for AS 708). The ionophores also differ in their ability to mediate Li⁺ membrane permeation, the order of decreasing potency being: AS 701≧AS 706>AS 702>AS 704≧AS 708. Of the five molecules studied, the AS 701 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.