Serotonin-2 Receptor Agonists Produce Anti-inflammatory Effects through Functionally Selective Mechanisms That Involve the Suppression of Disease-Induced Arginase 1 Expression

Introduction

Serotonin 5-HT2A receptor agonists have attracted interest for therapeutic applications beyond neuropsychiatry because these receptors are widely expressed in peripheral tissues, including endothelial, endocrine, and immune-related cells. Earlier preclinical work found that the phenylalkylamine agonist (R)-DOI has robust anti-inflammatory effects in vitro and in multiple rodent models, notably in an ovalbumin (OVA) sensitisation model of allergic asthma where intranasal, subbehavioural doses reduce airway hyperresponsiveness (AHR), mucus overproduction, collagen deposition and selectively suppress several OVA-induced proinflammatory mRNAs. At the same time, canonical measures of 5-HT2A activation such as Gq-mediated calcium flux, β-arrestin recruitment and behavioural potency do not predict anti-inflammatory efficacy, suggesting alternative downstream effectors may be responsible for peripheral anti-inflammatory actions. Using this background, Flanagan and colleagues compared two closely related phenylalkylamine 5-HT2A agonists—(R)-DOI and (R)-DOTFM—that have virtually identical receptor pharmacology and behavioural activity but differ in anti-inflammatory efficacy in the acute OVA asthma model. The central aim was to exploit these functionally selective ligands to identify physiological and molecular effectors associated specifically with anti-inflammatory outcomes, with a working hypothesis that proteins and pathways altered by (R)-DOI but not by (R)-DOTFM in OVA-treated animals would point to mechanisms essential for anti-inflammatory activity, including the possible involvement of arginase 1 (Arg1) suppression.