ADL5859 / Merck (MSD), Pfizer - LARVOL DELTA

Cryo-EM structure of small-molecule agonist bound delta opioid receptor-Gi complex enables discovery of biased compound. (PubMed, Nat Commun) - "In this study, we use cryo-electron microscopy (cryo-EM) to determine the structure of the δOR-Gi complex when bound to a small-molecule agonist (ADL5859)...Notably, we discover that the β-arrestin recruitment of δOR might be linked to reduced gastrointestinal motility. These insights enhance our understanding of δOR's structure, signaling pathways, and biological functions, paving the way for the structure-based drug discovery."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Epilepsy • Gastrointestinal Disorder • Pain

Development of a novel cell-based, In-Cell Western/ERK assay system for the high-throughput screening of agonists acting on the delta-opioid receptor. (PubMed, Front Pharmacol) - " Cells cultured in 96-well microassay plates were stimulated with three standard/selective DOPr agonists (SNC80, ADL5859, and DADLE) and a novel selective DOPr agonist (PN6047) to elicit a phospho-ERK response as an index of activation...This provides a basis for additional assay development to investigate opioid pharmacology. This protocol should be widely applicable for measuring ERK phosphorylation in any cell line and investigating other protein targets in GPCR drug discovery."

Journal • Addiction (Opioid and Alcohol) • Infectious Disease • Respiratory Diseases

Exploration of beta-arrestin isoform signaling pathways in delta opioid receptor agonist-induced convulsions. (PubMed, Front Pharmacol) - "To investigate our hypothesis, we characterized three different δOR agonists (SNC80, ADL5859, ARM390) in cellular assays and in vivo in wild-type and β-arrestin 1 and β-arrestin 2 knockout mice for seizure activity...Inhibition of the PI3K/AKT/mTOR signaling with honokiol but not PQR530, attenuated SNC80 seizure duration in β-arrestin 1 knockout, but honokiol did not reduce SNC80-induced seizures in wild-type mice. Ultimately, our results indicate that β-arrestin 2 is correlated with δOR agonist-induced seizure intensity, but that global β-arrestin 1 knockout mice are a poor model system to investigate their mechanism of action."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Epilepsy • Mental Retardation • Psychiatry • ARRB1

To probe the activation mechanism of the Delta opioid receptor by an agonist ADL5859 started from inactive conformation using molecular dynamic simulations. (PubMed, J Biomol Struct Dyn) - "The putative key residues (W274, D95, V267, L139, V263, M142, T260, R146, R258 and others) involving in the activation pathway were identified through the conventional molecular switch analysis and a pairwise distance analysis, which provides a short list for experimental mutagenesis study. These insights will facilitate further development of therapeutic agents targeting the DOR.Communicated by Ramaswamy H. Sarma."

Journal • Addiction (Opioid and Alcohol) • Pain

To probe the activation mechanism of the delta opioid receptor by an agonist ADL5859 started from an inactive conformation using molecular dynamic simulations (ACS-Sp 2022) - "The putative key residues involving in the activation were identified through the conventional molecular switch analysis and a pairwise distance analysis. These insights will facilitate further development of therapeutic agents targeting the DOR."

Addiction (Opioid and Alcohol) • Pain