[Molecular pharmacologic approaches to functional analysis of new biological target molecules for drug discovery]

This review focuses on two pharmacologic approaches to the functional evaluation of new target molecules for drug discovery. One is the development of a novel specific antagonist of the Na(+)-Ca(++) exchanger (NCX) SEA0400. The other is a comprehensive analysis of the functions of pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide ligand for G protein-coupled receptors. NCX is the one of the last target molecules regulating the cellular Ca(++) concentration. There was no efficient way to address the pathophysiologic roles of NCX until a specific antagonist, 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400), was developed. Our recent studies using SEA0400 clearly showed the possible roles of NCX in several pathologic states of cardiovascular and nervous tissues. In our second approach including gene-targeting methods, we found new, unexpected roles of PACAP in higher brain functions, such as psychomotor, cognition, photoentrainment, and nociception. Based on these experimental findings, a genetic association study in schizophrenia patients revealed that the single-nucleotide polymorphisms of the PACAP gene are significantly associated with the hypofunction of the hippocampus. Regarding the peripheral roles of PACAP, we found that PACAP is involved not only in the regulation of insulin secretion in pancreatic islets, but also in the regulation of islet turnover. In subsequent phenotypic analysis of PACAP transgenic mice, we identified novel candidate genes that probably have promising functional roles.