Title:The Neurokinins: Peptidomimetic Ligand Design and Therapeutic Applications
VOLUME: 27 ISSUE: 9
Author(s):Charlène Gadais and Steven Ballet*
Affiliation:Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussels, Pleinlaan 2, B-1050 Brussels, Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussels, Pleinlaan 2, B-1050 Brussels
Keywords:Neurokinin, ligand, antagonist, peptidomimetic, small heterocyclic scaffold, drug design.
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.
