Pharmacology of a k-opioid receptor ligand with a new chemotype

Modulating the GPCR k-opioid receptor is a promising strategy for treating various human diseases, where receptor activation shows potential for treating pain without causing respiratory depression or risk of overdose of conventional µ-opioid analgesics, and receptor antagonism is associated with beneficial effects for the treatment of mood and psychiatric diseases, and drug addictive disorders.

Combining experimental pharmacology (binding and functional in vitro assays, and behavioral nociceptive models) and computational chemistry (molecular docking, molecular dynamics simulations and dynamic pharmacophore (dynophore) generation, Compound A (4-[(2,3-dichlorophenyl)methylamino]-2-methylquinoline-8-carboxamide)) was identified as a novel k-opioid receptor antagonist, with a structurally distinct scaffold compared to the so far known k-opioid receptor ligands. Compound A selectively binds at the human k-opioid receptor and it shows k-opioid receptor antagonism in vitro and in vivo. The k-opioid receptor in vitro antagonism of Compound A was demonstrate based on the lack in inducing G protein activation upon ligand binding to the receptor expressed in CHO cells in the [35S]GTPγS binding assay, in contrast to the high potency and stimulatory effect shown by the prototypical k-opioid agonist U69,593. Behavioral investigations in mice established the in vivo k-opioid receptor antagonist properties of Compound A after subcutaneous administration, based on its capability to effectively reverse the antinociceptive effects of the prototypical k-opioid agonist, U50,488, in two pain models, the writhing assay and the formalin test. Furthermore, Compound A shows favorable physicochemical features and a better capability to enter the CNS. 

Compound A represents a valuable starting point for chemical optimization toward the development of innovative drugs targeting the k-opioid receptor as potential therapeutics for human conditions where the k-opioid system has a key function including mood, psychiatric and addictive disorders (antagonists), or pain conditions (agonists).

The dataset includes experimental in vitro and in vivo pharmacological data on Compound A, as a k-opioid receptor ligand with a new chemotype.