Assessing the Activity of Synthetic Opioid AH-7921 and U-47700 Analogs in Cloned Human Mu-Opioid Receptor Expressing Fibrosarcoma HT-1080 Cells

• NCJ Number: 253267
• Journal: Faseb Journal Volume: 32 Issue: 1 Dated: 2018
• Author(s): Tom Hsu; Jayapal Mallareddy; Kayla Yoshida; Tim Lee; Edna Kembol; Emily Park; John Krstenansky; Alexander Zambon
• Date Published: 2018
• Length: 19 pages
• Grant Number(s): 2016-R2-CX-0059
• Agencies: NIJ-Sponsored
• Publication Type: Research (Applied/Empirical); Report (Study/Research); Report (Grant Sponsored); Program/Project Description

Annotation

This study developed a stable amino terminal HA-tagged hOPRM1 expressing human fibrosarcoma (HT1080) cell line for determining the pharmacology of a panel of opioids analogs derived from synthetic opioids AH-7921 and U-47700.

Abstract

Although important for their antinociceptive properties in medicine, opioids are commonly abused in America due to easily accessible opiate prescription pain medication. Classic opioids can induce adverse side effects, such as gastrointestinal dysfunction and fatal respiratory depression, the latter of which is a key underlying factor contributing to the rising rates of lethality of opioid abuse. New synthetic opioids are emerging on the black market, many of which have not been characterized for structure activity relationships at human mu-opiate receptors (hOPRM1). The rise of new synthetic opioids complicates the opioid crisis in America as they often escape the traditional illicit drug classifications established by law enforcement and may be more potent and lethal than conventional molecules. The current study verified expression of hOPRM1 by Western blot and immunocytochemistry. Assessing the morphine response in this cell line revealed that morphine EC50 (39.3 nM) was comparable to published findings and were naloxone reversible, thereby validating this cell line. The analogs were assessed for their ability to suppress forskolin-induced cyclic AMP (cAMP) levels in a hOPRM1-dependent manner, revealing a subset of structurally-related analogs showing functional activity. The preliminary results of this study indicate that some of the synthetic opioid analogs are likely to have abuse potential based on their ability to bind to and activate the human OPRM1 receptor. (publisher abstract modified)