Identification of 1,3,8-triazaspiro[4.5]decane-2,4-dione Derivatives as a Novel Delta Opioid Receptor-Selective Agonist Chemotype

Abstract

Delta opioid receptors hold potential as a target for neurological and psychiatric disorders, yet no delta opioid receptor agonist has proven efficacious in critical phase II clinical trials. The exact reasons for the failure to produce quality drug candidates for the delta opioid receptor is nuclear. However, it is known that certain delta opioid receptor agonists can induce seizures and exhibit tachyphylaxis. Several studies have suggested that those adverse effects are more prevalent in delta agonists that share the SNC80/BW373U86 chemotype. There is a need to find novel lead candidates for drug development that have improved pharmacological properties to differentiate them from the current failed delta agonists. Our objective in this study was to identify novel delta opioid receptor agonists. We used a beta-arrestin assay to screen a small GPCR-focused chemical library. We identified a novel chemotype of delta opioid receptor agonists, that appears to bind to the orthosteric site based of docking and molecular dynamic simulation. The most potent agonist hit compound is selective for the delta opioid receptor over a panel of 167 other GPCRs, is slightly biased towards G-protein signaling and has anti-allodynic efficacy in a complete Freund's adjuvant model of inflammatory pain in C57BL/6 male and female mice. The newly discovered chemotype contrasts with molecules like SNC80 that are highly efficacious beta-arrestin recruiters and may suggest this novel class of delta opioid receptor agonists could be expanded on to develop a clinical candidate drug. Significance Statement Delta opioid receptors are a clinical target for various neurological disorders, including migraine and chronic pain. Many of the clinically tested delta opioid agonists share a single chemotype, which carries risks during drug development. Through a small-scale high throughput screening assay, we identified a novel delta opioid receptor agonist chemotype, with anti-allodynic efficacy which may serve as alternative for the current clinical candidates.

Keywords: Arrestins; computer modeling and simulation; high throughput screening; nociceptin/orphanin FQ; opioid receptors; signal transduction.