We have recently described a class of systemically active inhibitors of the intracellular activity of fatty acid amide hydrolase (FAAH) and traced extensive structure-activity relationships. These compounds, characterized by an N-alkyl carbamic acid O-aryl ester structure, exert potent anxiolytic-like effects in animal models. In the present study, possible relationships between mass spectrometric parameters (related to the propensity of the C(O)--O bond to be cleaved) and FAAH-inhibitory potency were tested. With this aim, a set of our products was analyzed by electrospray ionization mass spectrometry and the protonated molecules were decomposed by low-energy collisions. The experiments were performed by ion trap mass spectrometry, which led to a step-by-step energy deposition, thus favouring the lowest critical energy decomposition channels. For all compounds, breakdown curves relative to [MH](+) ions and to the fragment implying C(O)--O bond cleavage were obtained. The crossing point between these curves was related to the energetics of decomposition and the values found for the investigated compounds were linearly correlated (r(2) = 0.797) with their FAAH-inhibitory activity. This indicates that the energetics of the C(O)--O bond cleavage may be relevant in explaining FAAH inhibition.
