Combinatorial methods for the synthesis of new drug substances require high-throughput techniques for evaluation of structure-activity relationships. Microtiter plates with immobilized target receptors can rapidly reduce 1000's of possibilities to 100's of candidates. However, the next level of screening has proven to be more difficult and tedious. The goal of the project is the creation of an on- line screening approach to expedite secondary screening. The new technology involves immobilized biopolymer HPLC columns containing immobilized receptors or enzymes. Test compounds will be injected onto the IBC and chromatographed using standard HPLC techniques. The compounds will differntially adhere to the IBC according to their relative affinity for the immobilized biopolymer. The biopolymer-bound compounds will be sequentially displaced using a characterized ligand and the liberated compounds directed on-line into a mass spectrometer. Thus a large series of compounds can be rapidly screened for their relative affinities for the immobilized receptor with concurrent identification of molecular structures. The objective of the project is to develop prototypic IBCs using calcium channel receptors.
