Neurokinin-1 receptor-based bivalent drugs in pain management: The journey to nowhere?

Publication date: Available online 20 November 2018Source: Pharmacology & TherapeuticsAuthor(s): Patrycja Kleczkowska, Katarzyna Nowicka, Magdalena Bujalska-Zadrozny, Emmanuel HermansAbstractHybrid compounds (also known as chimeras, designed multiple ligands, bivalent compounds) are chemical units where two active components, usually possessing affinity and selectivity for distinct molecular targets, are combined as a single chemical entity. The rationale for using a chimeric approach is well documented as such novel drugs are characterized by their enhanced enzymatic stability and biological activity. This allows their use at lower concentrations, increasing their safety profile, particularly when considering undesirable side effects.In the group of synthetic bivalent compounds, drugs combining pharmacophores having affinities toward opioid and neurokinin-1 receptors have been extensively studied as potential analgesic drugs. Indeed, substance P is known as a major endogenous modulator of nociception both in the peripheral and central nervous systems. Hence, synthetic peptide fragments showing either agonism or antagonism at neurokinin 1 receptor were both assigned with analgesic properties. However, even though preclinical studies designated neurokinin-1 receptor antagonists as promising analgesics, early clinical studies revealed a lack of efficacy in human. Nevertheless, their molecular combination with enkephalin/endomorphin fragments has been considered as a valuable ap...
Source: Pharmacology and Therapeutics - Category: Drugs & Pharmacology Source Type: research