A series of 3-aryl-3arylmethoxyazetidine analogs were found to be active (nM) for the serotonin transporter (SERT) receptor in rat brain tissue. The aim of the project is to find a dually active compound at both the SERT and dopamine (DAT) transporter receptors, which could be used in the field of psychotherapeutics. A four- or five-step synthesis starting from 1-Boc-3-azetidinone was used for production of these 3-aryl-3-arylmethoxyazetidinone derivatives. Binding studies for SERT and DAT were completed by competitive inhibition against [3H]citalopram and [3H]WIN 35,428 , respectively, in rat brain tissue. To date, the 3-phenyl-3-(3,4-dichlorophenyl)methoxyazetidine analog (R =H, X = H, Y = 3,4-Cl2) was found to be the most active at the SERT receptor (Ki = 4.5 nM)  in in vitro binding studies, while having little DAT affinity (Ki = 2914 nM). These preliminary SAR studies indicate that the 3-aryl-3arylmethoxyazetidine scaffold is feasible for the development of SERT ligands with variable DAT affinity.

3-Aryl-3-arylmethoxyazetidines: A new series of high affinity ligands for monoamine transporters

246th National Meeting (2013)

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