Anandamide, an endocannabinoid, is linked to the regulation of stress, pain and inflammation. It activates cannabinoid receptors (CB receptors) on the cell surface, leading to the relief of pain and stress. Anandamide can also enter cells by diffusion, carried by fatty acid binding proteins (FABPs) through cytoplasm and degraded by fatty acid amide hydrolase (FAAH). Inhibition of these tissue specific FABPs would arrest the transportation and hydrolysis of the endocannabinoid, resulting in elevated extracellular anandamide levels and anti-inflammatory and anti-nociceptive effects. Targeting on FABP 5 (epidermal) and FABP 7(brain), pioneering work which includes high-throughput virtual screening, fluorescence displacement assay, and high solution protein X-ray structure determinations, has been done from our laboratories. It demonstrated that α-truxillic acid 1-naphthyl mono-ester (SB-FI-26) exhibits strong binding to FABP5 and potent anti-nociceptive effects in mice. Based on the binding energy score from Autodock, a series of a-/γ- truxillic esters were synthesized and their binding affinity towards FABP 5 and FABP 7 were evaluated in vitro. Based on preliminary in vitro data, we explored SAR and developed new inhibitors with high potency and specificity.

Design, synthesis and SAR study of truxillic acid-based fatty acid binding protein inhibitors as anti-nociceptive and anti-inflammatory drugs

253rd National Meeting (2017)

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