Tryptamide (nicotredole) revisited: re-examining a forgotten anti-inflammatory agent by large-scale target profiling
Katarzyna Szczepańska1, Tadeusz Karcz2, Ryszard Bugno1
1Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, Kraków, 31-343, Poland.
Background:
Tryptamide (nicotredole) is a clinically investigated small molecule that was previously reported to possess anti-inflammatory, antirheumatic, and sedative properties, yet its molecular targets and mechanism of action remain poorly understood. Moreover, despite historical pharmacokinetic studies, its absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile has not been comprehensively evaluated using contemporary methodologies.
Methods:
Tryptamide was resynthesized and subjected to a panel of in vitro ADMET assays, including PAMPA permeability, Caco-2 transport, P-glycoprotein interaction, CYP3A4 inhibition, metabolic stability in human liver microsomes, and hepatotoxicity assessment in HepG2 cells. To investigate its mechanism of action, the compound was profiled against 135 biological targets using Eurofins CNS Target Panel™ and InflamEnzyme Panel™ platforms, followed by selected concentration-response studies and additional assays relevant to neuroinflammation and neurodegeneration.
Results:
Tryptamide exhibited favorable in vitro developability characteristics, including high intestinal permeability, limited interaction with P-glycoprotein, high metabolic stability in human liver microsomes, and low cytotoxicity in HepG2 cells under the tested conditions. The compound inhibited CYP3A4 (IC50 = 2.30 ± 0.39 µM), whereas follow-up evaluation of the thromboxane synthase screening hit revealed weak inhibitory activity (IC50 = 78 µM). Broad target profiling revealed remarkably limited pharmacological activity, with only four targets showing > 50% inhibition at 10 µM: CYP2C19, CYP3A4, thromboxane synthase, and the serotonin 5-HT2C receptor. Additional studies demonstrated no meaningful activity toward FAAH, TNFα-induced necroptosis, or β-amyloid aggregation.
Conclusions:
Contemporary re-evaluation revealed a favorable in vitro ADMET profile but failed to identify a convincing molecular mechanism underlying the reported pharmacological effects of tryptamide. The findings highlight both the utility and limitations of modern target profiling approaches in the reassessment of historical drug candidates.
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