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      Design of Peptide and Peptidomimetic Ligands with Novel Pharmacological Activity Profiles

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      Annual Review of Pharmacology and Toxicology
      Annual Reviews

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          Abstract

          <p class="first" id="P1">Peptide hormones and neurotransmitters are of central importance in most aspects of intercellular communication and are involved in virtually all degenerative diseases. In this review, we discuss physicochemical approaches to the design of novel peptide and peptidomimetic agonists, antagonists, inverse agonists, and related compounds that have unique biological activity profiles, reduced toxic side effects, and, if desired, the ability to cross the blood-brain barrier. Designing ligands for specific biological and medical needs is emphasized, as is the close collaboration of chemists and biologists to maximize the chances for success. Special emphasis is placed on the use of conformational (φ-ψ space) and topographical (χ space) considerations in design. </p>

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          Most cited references91

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          Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders.

          Despite G-protein-coupled receptors (GPCRs) being among the most fruitful targets for marketed drugs, intense discovery efforts for several GPCR subtypes have failed to deliver selective drug candidates. Historically, drug discovery programmes for GPCR ligands have been dominated by efforts to develop agonists and antagonists that act at orthosteric sites for endogenous ligands. However, in recent years, there have been tremendous advances in the discovery of novel ligands for GPCRs that act at allosteric sites to regulate receptor function. These compounds provide high selectivity, novel modes of efficacy and may lead to novel therapeutic agents for the treatment of multiple psychiatric and neurological human disorders.
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            Conformation of Polypeptides and Proteins

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              Allosteric modulation of G protein-coupled receptors.

              The past decade has witnessed a significant growth in the identification of allosteric modulators of G protein-coupled receptors (GPCRs), i.e., ligands that interact with binding sites that are topographically distinct from the orthosteric site recognized by the receptor's endogenous agonist. Because of their ability to modulate receptor conformations in the presence of orthosteric ligand, allosteric modulators can "fine-tune" classical pharmacological responses. This is advantageous in terms of a potential for engendering greater GPCR subtype-selectivity, but represents a significant challenge for detecting and validating allosteric behaviors. Although allosteric sites need not have evolved to accommodate endogenous ligands, there are a number of examples of where such modulators have been shown to contribute to physiological or pathophysiological processes. Studies are also beginning to unravel the structural basis of allosteric modulation of GPCRs. It remains to be determined whether such modulation represents interactions within monomers versus across dimers.
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                Author and article information

                Journal
                Annual Review of Pharmacology and Toxicology
                Annu. Rev. Pharmacol. Toxicol.
                Annual Reviews
                0362-1642
                1545-4304
                January 06 2013
                January 06 2013
                : 53
                : 1
                : 557-580
                Article
                10.1146/annurev-pharmtox-010510-100456
                5079645
                23294313
                27228482-2ce4-48e2-86b8-ebb9f5ca0f96
                © 2013
                History

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