The hypothesis that privileged structures bind near the "active site" of receptors and that they bind to both peptide and nonpeptide receptors was intriguing. It suggested to us that peptide agonists and antagonists might be achieved by appending small peptide units onto privileged structures. Hopefully, there would be some overlap with the peptide agonist binding area. If not, such derivatization could still be worthwhile since amino acid side-chains obviously provide a rich diversity of functionality to interact with proteins. In the case of the spiroindanylpiperidine unit, single capped amino acids were chosen for derivatization in part since it was known from the benzolactams that a large structural unit was not required to produce agonist activity. One of the highlights of this derivatization project was compound 19 (Table 2) whose EC50 = 50 nM in the rat pituitary GHS assay was remarkable especially since it was tested as an unseparated mixture of four diastereomers. In retrospect, this excellent activity was ascribed to the fact that each component of 19 was present in GHS active compounds. The spiroindanylpiperidine came from the screening lead 10, tryptophan is a key amino acid in the GHRPs and the quinuclidene part-structure was present in an unpublished Merck screening lead. That these modular units are arranged in compound 19 in the proper order, at the proper distances and with acceptable linking groups was quite fortuitous (54). Nor was it predictable that compound 19 would be an agonist since, at the time, the other known spiropiperidines were receptor antagonists.
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