Utilization of an intramolecular hydrogen bond to increase the CNS penetration of an NK(1) receptor antagonist.

This paper describes the synthesis and physical and biological effects of introducing different substituents at the alpha-position of the tryptophan containing neurokinin-1 receptor antagonist [(R)-2-(1H-indol-3-yl)-1-methyl-1-((S)-1-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzofuran-2-ylmethyl ester (CI 1021). The described compounds all exhibit less than 5 nM binding affinities for the human neurokinin-1 receptor and selectivity over the tachykinin NK(2) and NK(3) receptor subtypes. Application of variable temperature nuclear magnetic resonance spectroscopy studies of the amide and urethane protons was utilized to determine the existence of an intramolecular hydrogen bond.

Structure-based design in drug discovery--the application of a peptoid drug design strategy for the development of non-peptide neuropeptide receptor ligands.

Over the last decade the increasing availability of metabolically- stable non-peptide antagonists targeted at neuropeptide receptors has led directly to a more thorough understanding of the role of neuropeptides in mammalian physiology. By far the majority of these non-peptide neuropeptide receptor antagonists thus far disclosed have been developed from leads identified from broad screening of company compound files or natural product collections, and may thus bear little obvious structural resemblance to the endogenous peptide ligand. This review will focus on an alternative structure-based approach to non-peptide neuropeptide receptor ligand design, referred to as the 'peptoid' drug design strategy, in which an appreciation of the structure of the neuropeptide is the key to the success of this approach.

'Targeted' molecular diversity: design and development of non-peptide antagonists for cholecystokinin and tachykinin receptors.

A drug design strategy to non-peptide small molecule antagonists of neuropeptides is described that targets the molecular diversity which exists in the 'privileged' data set of the physico-chemical properties represented by the side-chains of the 20 genetically encoded amino acids. The strategy is exemplified by the design of a selective and high affinity cholecystokinin CCK-A antagonist PD 140548, CCK-B antagonist CI-988 (formerly PD 134308) tachykinin NK-1 antagonist PD 154075 and NK-2 antagonist Cam-2291. The NK-3 antagonists, PD 157672 and the non-peptide PD 161182, were developed from an information-rich dipeptide library constructed from 256 N-protected dipeptides and 64 hydrophobic biased dipeptides.

Use of a dipeptide chemical library in the development of non-peptide tachykinin NK3 receptor selective antagonists.

The use of a dipeptide library as the source of a micromolar chemical lead compound for the human tachykinin NK3 receptor is described. The screening of a dipeptide library through a cloned human NK3 receptor binding assay resulted in the identification of Boc(S)Phe(S)PheNH2 (1), which has subsequently been developed, following a 'peptoid' design strategy, into a series of high-affinity NK3 receptor selective antagonists. The structure-activity relationship of the C-terminal portion of this dipeptide lead was first explored and led to the identification of the urea derivative Boc(S)Phe(R)alphaMePheNH(CH2)7NHCONH2 (41, PD157672).

Two classes of structurally different antagonists display similar species preference for the human tachykinin neurokinin3 receptor.

Two classes of structurally different tachykinin neurokinin3 (NK3) antagonists were used to evaluate species difference in antagonist binding between human and rat NK3 receptors. In competition binding experiments with [125I-MePhe7]NKB as radioligand, PD 154740, PD 157672, SR 48968, and SR 142801 displayed lower Ki values for the human NK3 receptor (40 +/- 4, 12 +/- 1,350 +/- 50, and 0.40 +/- 0.

Rational design of high affinity tachykinin NK1 receptor antagonists.

The rational design of a non-peptide tachykinin NK1 receptor antagonist, [(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3)P h (28, PD 154075) is described. Compound 28 has a Ki = 9 and 0.35 nM for the NK1 receptor binding site in guinea-pig cerebral cortex membranes and human IM9, cells respectively (using [125I] Bolton-Hunter-SP as the radioligand).