Abstract
Publisher Summary The reason that nonpeptide ligands are sought resides mainly in the well documented limitations of peptides as drugs— that is, poor oral bioavailability, poor in vivo half life, and poor central nervous system (CNS) penetration. The historical development of this field can be traced back to the discovery of the endogenous opioid peptides, for example, metenkephalin: Tyr-Gly-Gly-Phe-Met. Sufficient work has been published in this area to review not only the structures of nonpeptide ligands but also the strategies that have led to their discovery. In this regard, the pioneering conceptual contribution of Ariens and Farme deserves special mentions. The broad screening approach, which includes natural product sources and company files, has been facilitated by the automation of high throughput receptor binding assays. Many of the nonpeptide ligands in this chapter are reported to have been discovered with the aid of a broad screening approach. The other two strategies incorporate an element of design based on the structure and the peptide-structure–activity relationship (SAR) data of a known peptide antagonist or an endogenous peptide agonist. Currently, the two most successful strategies for the discovery of nonpeptide antagonists for neuropeptide receptors are broad screening of natural products or chemical files in an automated receptor binding assay usually followed by chemical lead optimization and “design” starting from the peptide structure of a known antagonist or the endogenous agonist. The strategies described in this chapter can facilitate the discovery of nonpeptide ligands for other neuropeptide receptors and in principle they may also be applied to additional receptor targets for which there are peptide ligands.
Published Version
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