XLR-11

XLR-11, also known as 5F-UR-144, is a synthetic cannabinoid in the tetramethylcyclopropylindole family. It is the terminally fluorinated analogue of UR-144 and acts as a full agonist at CB₁ and CB₂ receptors. XLR-11 was identified in herbal smoking products in the early 2010s and has been associated with acute intoxications, including cases of acute kidney injury.

Chemistry and identification

XLR-11 is (1-(5-fluoropentyl)-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone. It contains the same tetramethylcyclopropyl ketone group as UR-144, but has a fluorine atom at the terminal carbon of its N-pentyl chain. UNODC lists XLR-11, 5-fluoro-UR-144 and 5F-UR-144 as names for the same structure (UNODC substance record: XLR-11).

Pharmacology

XLR-11 binds to CB₁ and CB₂ receptors with low-nanomolar affinity and acts as a full agonist in the reported assays. In animal experiments it produced THC-like responses, including antinociception, hypothermia, catalepsy and suppression of locomotor activity. These effects were blocked by a CB₁ antagonist (Wiley and colleagues, 2013).

A comparative study of fluorinated synthetic cannabinoids found agonist activity at both CB₁ and CB₂ receptors. Terminal fluorination generally increased CB₁ potency in vitro, although the animal telemetry results did not show a consistent corresponding increase in potency (Banister and colleagues, 2015).

Metabolism

Human hepatocyte research identified more than 25 XLR-11 metabolites. The main products included carboxylated and hydroxylated compounds, glucuronide conjugates and metabolites formed after oxidative defluorination. Defluorination produces metabolites also associated with UR-144, which can complicate interpretation if a laboratory relies on shared metabolic markers alone (Wohlfarth and colleagues, 2013).

CYP3A4 was identified as the major enzyme involved in metabolism of both XLR-11 and UR-144, with smaller contributions from CYP1A2 and CYP2C19 (CYP450-mediated metabolism of UR-144 and XLR-11, 2015).

Reported effects and clinical findings

XLR-11 has been detected in emergency and forensic investigations involving synthetic cannabinoid intoxication. A retrospective clinical review found it among the more frequently identified compounds in a series of patients presenting with altered mental status and other atypical clinical features (Retrospective chart review of synthetic cannabinoid intoxication, 2018).

Case reports have also associated XLR-11-containing products with acute kidney injury. In several reports, other synthetic cannabinoids or substances were present, so the contribution of XLR-11 alone could not be established with certainty.

Toxicity and research limitations

XLR-11 has a documented history of clinical and forensic detection, but human toxicokinetic data remain limited. Its active receptor profile, extensive metabolism and formation of shared metabolites complicate the interpretation of biological samples. There is no reliable concentration threshold that predicts the severity of intoxication.

Related compounds

XLR-11 is related to UR-144, XLR-12 and other tetramethylcyclopropylindoles. It is the 5-fluoropentyl analogue of UR-144.