A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABAA Receptor

Abstract

Analgesic and anti-inflammatory properties mediated by the κ opioid receptor (KOR) have been reported for oxadiazole imidazodiazepines. Affinities determined by radioligand competition assays of more than seventy imidazodiazepines using cell homogenates from HEK293 cells that overexpress KOR, µ opioid receptor (MOR), and δ opioid receptor (DOR) are presented. Affinities to synaptic, benzodiazepine-sensitive receptors (BZR) were determined with rat brain extract. The highest affinity for KOR was recorded for GL-I-30 (Ki of 27 nM) and G-protein recruitment was observed with an EC50 of 32 nM. Affinities for MOR and DOR were weak for all compounds. Ester and amide imidazodiazepines were among the most active KOR ligands but also competed with 3H-flunitrazepam for brain extract binding, which is mediated predominately by gamma aminobutyric acid type A receptors (GABAAR) of the α1-3β2-3γ1-2 subtypes. Imidazodiazepines with carboxylic acid and primary amide groups did not bind KOR but interacted strongly with GABAARs. Pyridine substitution reduced KOR affinity. Oxadiazole imidazodiazepines exhibited good KOR binding and interacted weakly with BZR, whereas oxazole imidazodiazepines were more selective towards BZR. Compounds that lack the imidazole moiety, the pendent phenyl, or pyridine substitutions exhibited insignificant KOR affinities. It can be concluded that a subset of imidazodiazepines represents novel KOR ligands with high selectivity among opioid receptors.

Synthesis and Receptor Binding Studies of α5 GABAAR Selective Novel Imidazodiazepines Targeted for Psychiatric and Cognitive Disorders

“…The kappa opioid receptors (KOR), µ and δ opioid receptors (MOR and DOR), and nociception opioid receptor (NOP) fall under the family of opioids receptors [ 81 ]. It has been reported that oxadiazole imidazodiazepines can mediate analgesic and anti-inflammatory properties mediated also by the κ opioid receptor (KOR) [ 82 ]. The binding at KOR is usually silent.…”

Mechanism and Management of Fentanyl-Induced Cough

“…Classical opioid receptors can be divided into three types: μ, κ and σ. As the most widespread opioid receptors, µ receptors have been confirmed to be widely involved in analgesia and sedation as well as other processes (Li et al, 2020;Valentino and Volkow, 2018) (Figure 2). As µ receptor agonists, fentanyl analogs can bind and activate μ1 receptors and play an analgesic role.…”

Development of Inhaled GABAA Receptor Modulators to Improve Airway Function in Bronchoconstrictive Disorders

“…We can conclude that the conjugation of MIDD0301 at the carboxyl group can generate amides that retain GABA A R affinity. Other examples of MIDD0301-derived amides and esters have been reported. − Furthermore, compounds like PI320 have excellent physicochemical properties, quick onset of smooth muscle relaxation, and potently alleviate AHR. PI320 can be nebulized as an aqueous solution achieving high lung concentrations and a good half-life.…”