Amazing stuff!
"Research has provided concrete structural evidence that ketamine has opioidic tendencies.
Until recently, ketamine’s pain-reducing and sedatory abilities have been predominantly put down to its ability to block the N-methyl-D-aspartate receptors (NMDAR) in the brain.
While studies have suggested some relationship between ketamine and the opioid pathway, until now, no study has visualized ketamine activating opioid receptors. Looking at how NMDAR and opioid receptor signalling works together to drive ketamine's therapeutic effects could help guide the next generation of drugs ..."
From the abstract:
"Ketamine offers rapid relief for treatment-resistant depression and severe pain in the clinic, providing immediate benefits that traditional medications often fail to deliver.
While its antagonistic action at the N-methyl-D-aspartate receptor (NMDAR) is a key mechanism, ketamine’s dual nature as both a promising treatment and a drug with abuse potential suggests its therapeutic effects extend beyond NMDAR inhibition.
Here we provide structural evidence of human opioid receptors bound to ketamine and its parent analog phencyclidine (PCP), supporting that both ligands can directly bind and activate opioid receptors.
The structures, together with site-directed mutagenesis and structure–activity relationship studies, identify key motifs involved in ketamine and PCP recognition and efficacy modulation.
Furthermore, we determine the structure of the ligand-free state of human κ opioid receptor, revealing molecular details before ligand engagement.
Compared to PCP, ketamine displays more notable binding dynamics in the orthosteric site that may contribute to its unique pharmacology at opioid receptors. Our findings highlight the importance of including opioid receptors to fully understand ketamine’s versatility in clinical settings."
Fig. 1: Cryo-EM structures of human opioid receptors bound to ketamine and PCP.
Fig. 3: Unique pharmacology of 3-OH-PCP.
No comments:
Post a Comment