Elucidating Anti‐Inflammatory Signaling Paradigm at the 5‐HT 2A Receptor

Summary

Classical serotonergic psychedelics are being re-examined as treatments for various diseases. While most research focuses on their central nervous system effects, previous work suggests that serotonin 2A receptor (5-HT2AR) agonists can modulate TNF-alpha-mediated inflammatory responses in the periphery. This study characterizes signaling pathway activation for a panel of 5-HT2AR ligands from three chemical classes: tryptamines, ergolines, and phenethylamines. Initial results examining the canonical Gαq pathway and β-arrestin2 recruitment showed no significant correlation between potency or efficacy and anti-inflammatory activity in vivo. Ongoing studies are examining additional GPCR-mediated signaling via cAMP accumulation to understand the structural basis for biased signaling and inform drug design.

Study at a glance

Abstract

Given the recent resurgence of clinical interest in the application of classical serotonergic psychedelics as treatment for various disease states, a comprehensive analysis of the structure‐activity relationship (SAR) is necessary to fully understand the differential expression of behavioral and physiological effects elicited by these compounds. While the field is mostly focused on action within the central nervous system, previously published data from the Nichols laboratory supports the use of serotonin (5‐hydroxytryptamine; 5‐HT) 2A receptor (5‐HT 2A R) agonists as potent modulators of tumor necrosis factor alpha (TNF‐α)‐mediated inflammatory responses in the periphery. Whereas whole organism models will provide insight into the physiological response profile, the mechanism of action and structural basis mediating the anti‐inflammatory activity have yet to be elucidated on a molecular level. In this study, we are characterizing the signaling pathway activation profile of a comprehensive panel of 5HT 2A R ligands comprising three chemical classes: tryptamines, ergolines, and phenethylamines. We hypothesize that a distinct signaling pathway elicited by 5‐HT 2A R activation is mediating the differential anti‐inflammatory response to these ligands. With this data, the varying degree of effector pathway bias can also be determined for each ligand, which, from a pharmacological standpoint, will support better understanding of adverse and favorable therapeutic activities, as well as, to inform structure‐activity studies and drug candidate selection matrices. Initial results from examination of the canonical Gα q pathway – using a calcium mobilization measure – and recruitment of the multi‐adaptor protein β‐arrestin2 – using a luciferase reporter gene assay – exhibit no significant correlation between potency and efficacy for either pathway with in vivo measures of anti‐inflammatory activity. Ongoing studies are examining additional GPCR‐mediated signaling (G i , G s ) via comparative analysis of cAMP accumulation. The collective analysis of a comprehensive panel of 5HT 2A R ligands has never been examined in this fashion; thus, we aim to elucidate the SAR to inform drug design for novel molecules that are biased to pathways targeting a biologically therapeutic response. Support or Funding Information Eleusis PBC This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .