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The Neurokinins: Peptidomimetic Ligand Design and Therapeutic Applications.

Authors
  • Gadais, Charlène1
  • Ballet, Steven1
  • 1 Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussels, Pleinlaan 2, B-1050 Brussels, Belgium. , (Belgium)
Type
Published Article
Journal
Current medicinal chemistry
Publication Date
Jan 01, 2020
Volume
27
Issue
9
Pages
1515–1561
Identifiers
DOI: 10.2174/0929867325666180913095918
PMID: 30209994
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The neurokinins are indisputably essential neurotransmitters in numerous pathoand physiological events. Being widely distributed in the Central Nervous System (CNS) and peripheral tissues, their discovery rapidly promoted them to drugs targets. As a necessity for molecular tools to understand the biological role of this class, endogenous peptides and their receptors prompted the scientific community to design ligands displaying either agonist and antagonist activity at the three main neurokinin receptors, called NK1, NK2 and NK3. Several strategies were implemented for this purpose. With a preference to small non-peptidic ligands, many research groups invested efforts in synthesizing and evaluating a wide range of scaffolds, but only the NK1 antagonist Aprepitant (EMENDT) and its prodrug Fosaprepitant (IVEMENDT) have been approved by the Food Drug Administration (FDA) for the treatment of Chemotherapy-Induced and Post-Operative Nausea and Vomiting (CINV and PONV, respectively). While non-peptidic drugs showed limitations, especially in side effect control, peptidic and pseudopeptidic compounds progressively regained attention. Various strategies were implemented to modulate affinity, selectivity and activity of the newly designed ligands. Replacement of canonical amino acids, incorporation of conformational constraints, and fusion with non-peptidic moieties gave rise to families of ligands displaying individual or dual NK1, NK2 and NK3 antagonism, that ultimately were combined with non-neurokinin ligands (such as opioids) to target enhanced biological impact. Copyright© Bentham Science Publishers; For any queries, please email at [email protected]

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