The Neurokinins: Peptidomimetic Ligand Design and Therapeutic Applications

Abstract

The neurokinins are indisputably essential neurotransmitters in numerous patho- and physiological events. Being widely distributed in the central nervous system (CNS) and peripheral tissues, their discovery rapidly promoted them to drugs targets. 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 for 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 was combined with non-neurokinin ligands (such as opioids) to target enhanced biological impact.

Harnessing the Anti-Nociceptive Potential of NK2 and NK3 Ligands in the Design of New Multifunctional μ/δ-Opioid Agonist–Neurokinin Antagonist Peptidomimetics

“…Among those, MEN 15,596 or Ibodutant stood out as a NK2 antagonist with great potential for the treatment of abdominal pain [ 35 , 36 ], which ended up in clinical trials for IBS (Irritable Bowel Syndrome) therapy. Its parent compound, MEN 14,268, which mainly differs at the C -terminal basic appendage, displayed slightly reduced antagonism and NK2 affinity, but higher apparent permeability [ 13 ]. Considering synthetic feasibility, MEN 14,268 appeared more attractive.…”

“…For the purpose of the current study, MEN 14,268 was eventually simplified by replacing the benzothiophene unit with a simple benzylamine group, leading to a pseudo-peptidic NK2 antagonist pharmacophore SBL-OPNK-2 ( Figure 1 ). Finally, as a representative of a non-peptidic scaffold, Talnetant matched, as this compound combines good affinity (nanomolar range), selectivity, and antagonist activity of the NK3 receptor [ 13 ]. This small molecule, bearing a central quinoline core, exhibited great potential in inhibiting nociception associated with intestinal distension [ 37 ].…”

“…Via the pioneering discovery of Substance P (SP), a whole family of endogenous neuropeptides was unveiled and rapidly considered as an attractive target for brain-related disorders. The neurokinin ligands NKA and NKB, in particular, and their preferred transmembrane receptors, neurokinin-2 (NK2) and neurokinin-3 (NK3), respectively, both belonging to the GPCR family, are essentially present in the central nervous system (CNS) and the periphery, where they exert neuromodulatory activities in a wide range of patho- and physiological processes [ 12 , 13 ]. Their involvement in visceral nociception and inflammation, pain memory, and pain-induced stress response as well as neuroendocrine disorders motivated the design of several peptidic and non-peptidic drugs targeting NK2–NK3 receptors [ 13 , 14 , 15 ].…”

“…Considering both the non-exclusive interaction of the three neurokinin ligands with their receptors and their common involvement in major physiological events, the close synergistic activity between the opioid and neurokinin systems was recently reviewed [ 16 ]. Notably, a major interest in SP as a potent target in pain treatment was largely reflected by the numerous studies published in the last decade(s) [ 13 , 17 , 18 ]. Recently, our group also developed opioid agonist–neurokinin NK1 antagonist hybrids, which displayed promising activity in neuropathic pain models [ 19 , 20 ].…”