Rationale, Design, and Synthesis of Novel Phenyl Imidazoles as Opioid Receptor Agonists for Gastrointestinal Disorders

Abstract

A small series of novel, imidazoles 4 have been prepared that exhibit very good binding affinities for the delta and mu opioid receptors (ORs), as well as demonstrate potent agonist functional activity at the delta OR. Representative imidazole 4a (K(i) delta = 0.9 nM; K(i) mu = 55 nM; K(i) kappa = 124 nM; EC(50) delta =13-25 nM) was further profiled for OR related in vivo effects. Compound 4a reduced gastrointestinal (GI) propulsive motility in a dose-dependent and naloxone-reversible manner, based on the results of the mouse glass bead expulsion test (3, 5, and 10 mg/kg, ip) and the mouse fecal pellet output test (1 and 3 mg/kg, ip). Compound 4a showed no analgesic activity as measured by the mouse abdominal irritant test (MAIT) when dosed at 100 mg/kg, sc, but did show significant MAIT activity at doses of both 10 microg (40% inhibition) and 100 microg (100% inhibition) when dosed intracerebroventricularly (icv). Taken together, these in vivo results suggest that 4a acts peripherally when dosed systemically, and that these prototypical compounds may prove promising as medicinal leads for GI indications.

Construction of a Virtual Opioid Bioprofile: A Data-Driven QSAR Modeling Study to Identify New Analgesic Opioids

“…An external validation set that consisted of 20 approved opioid drugs, which were not in the training set for model development, was collected from ChEMBL . The opioid receptor binding activities of these compounds were collected from literatures to be compared to the model predictions. − External general drugs were retrieved from the DrugBank database for prediction and comparison purposes. After removing overlap compounds in the probe data set and external validation set, the remaining 2042 DrugBank compounds were also used for external predictions.…”

Multitargeted Opioid Ligand Discovery as a Strategy to Retain Analgesia and Reduce Opioid-Related Adverse Effects

“…The discovery of eluxadoline ( 38 ) (Figure ) was also inspired by mimicking the conformation of the enkephalin peptides ( 22 and 23 ) (Figure ). However, for eluxadoline ( 38 ), the central design scaffold was the imidazole ring system. , This work was expanded and refined by the same group to produce the ligand eluxadoline ( 38 ), with pharmacologic evaluations performed by the Hornby and Devi groups . Eluxadoline ( 38 ) bound with nM affinity at the human MOP receptor ( K i = 1.8 nM) and nM affinity at the rat DOP receptor ( K i = 1.3 nM) but much lower affinity at the human DOP receptor ( K i = 430 nM) (Table ) Importantly, eluxadoline ( 38 ) had a MOP agonist/DOP antagonist profile (Table ).…”

The modification of natural products for medical use

“…Finally eluxadoline ( 43 ) is validated as the final candidate. It is worthwhile to note that the presence of free carboxyl and amino groups in 43 yield a zwitterion that prevents the drug from being absorbed into the blood stream 19 .…”