Peptidomimetics receptors

Hypogonadotropic hypogonadism Gonadotropin-releasing hormone (GnRH) receptor GnRH peptidomimetic antagonist... 

Portoghese PS, Nagase H, Maloney Huss KE, Lin CE, Takemori AE. Role of spacer and address components in peptidomimetic 6 opioid receptor antagonists related to naltrindole. J Med Chem 1991 34 1715-1720. 

Our final peptidomimetic example is compound FR190997 (6.119), a mimic of bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg, see also Fig. 6.34) that has high affinity and selectivity for the human B2 receptor. Remarkably and in contrast to many analogues, FR190997 is a bradykinin... 

A form of peptidomimetics (a peptidomimetic is a compound that acts as a substitute for peptides in their interaction with receptors) is the formation of DKPs where amino acid residues are cyclized to form a stable ring structure. The design and development of peptidomimetics allows for the generation of new pharma-cotherapeutic agents with the potential of exerting a more desirable or favorable physiological response than its prototype. ... 

Ideally, a peptidomimetic agent should have one or more of the following properties (1) high specificity/ selectivity for a single receptor, (2) metabolic stability, (3) prolonged duration of action, (4) high receptor affinity and thus potency, (5) minimal adverse effects, and (6) good bioavailability. 

Recent examples of successful peptide-ligand based discoveries of drug-like peptidomimetics include the discovery of SST antagonists, or the discovery of non-peptidic antagonists of the recently deorphanized urotensin II receptor at Sanofi-Aventis. ° As illustrated in Fig. 3, Flohr etal. used 3D models of the NMR solution structure of cyclic peptide derivatives of Urotensin II as a template for virtual 3D pharmacophore searches which resulted into non-peptidic candidates for lead optimization. 

In the technique of post hoc design, a set of descriptors are built up by examination of a set of compounds active at a particular receptor family or sub-class. Normally, the set of drugs would be from a commercial database such as MDDR or the Merck Index, etc. and the descriptors would usually be substructural fragment or key based. One example would be the GPCR-PA+ sub-class referred to above, where BCUT descriptors have been used to aid the design of a focused library of aroimd 2000 compoimds based on 8 scaffolds. Libraries have also been constructed based on peptidomimetic principles as well as on the concepts of privileged structures. ... 

A. Giannis, T. Kolter, Peptidomimetics for receptor ligands—Discovery, development, and medical perspectives, Angew. Chem. Int. Ed. 32(9) (1993) 1244—1267. 

Peptidomimetics is an active branch of patterned synthesis. A notable family of tumor-avid peptides was derived from synthesis patterned on neurotensin, a peptide constituted of 13-amino acids. These synthetic peptides bind to the NT receptors expressed by many forms of cancer, which may serve to map the tumor, delivering radionuclides in situ (Waibel 2000). Molecules that, like the peptides, are constituted of repetitive blocks, are much simpler to synthesize than those composed of non-repetitive units. Given the powerful bioactivity, and improved stability on systemic administration, synthetic peptides may become rewarding it as it has been estimated, one in two men, and one in three women, will get cancer in their lifetime. 

R. M. Jones, P. D. Boatman, G. Semple, Y.-J. Shin, S. Y. Tamura (2003). Clinically validated peptides as templates for de novo peptidomimetic drug design at G-protein-coupled receptors. Curr. Opin. Pharmacol. 3 530-543. 

Historically, the major focus of peptidomimetic design has evolved from receptor-targeted drug discovery research and has not been directly impacted by an experimentally-determined 3D structure of... 

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