The objective of this project is to combine the tools of theoretical, physical and synthetic organic chemistry to produce and characterize electrochromic molecular probes of membrane potential. We plan to produce probes which absorb in the 500-700 nm region so as to increase the usefulness of the methodology in applications to various problems in electrophysiology. We also plan to produce probes which can label specific receptor sites or which can covalently label membrane components in an effort to determine localized potential changes mediating specific events in the cell. Several analogues of the 4-(p-aminostryryl)pyridinium (ASP) chromophore with more extended conjugated Pi-systems will be examined with molecular orbital theory and synthetically incorporated into probes. The spectral properties and responses to membrane potential of the probes will be characterized and calibrated with phospholipid vesicles and a hemispherical lipid bilayer system. The probes will the be screened and further characterized with squid axon and red blood cell preparations. More complex experiments are planned to monitor electrical activity in an awake animal brain and to determine the fast kinetic details of membrane potential changes mediated by the acetylcholine receptor. These two examples illustrate how the probes can be used to help solve basic research problems in physiology, on the one hand, and how they may eventually be applied to clinical diagnostic procedures on the other.
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