Alexander Alexei Greenfield

WAY-855 (3-amino-tricyclo[2.2.1.02.6]heptane-1,3-dicarboxylic acid): a novel, EAAT2-preferring, nonsubstrate inhibitor of high-affinity glutamate uptake.

The pharmacological profile of a novel glutamate transport inhibitor, WAY‐855 (3‐amino‐tricyclo[2.2.1.02.6]heptane‐1,3‐dicarboxylic acid), on the activity of the human forebrain glutamate transporters EAAT1, EAAT2 and EAAT3 expressed in stable mammalian cell lines and in Xenopus laevis oocytes is presented. WAY‐855 inhibited glutamate uptake mediated by all three subtypes in a concentration‐dependent manner, with preferential inhibition of the CNS‐predominant EAAT2 subtype in both cells and oocytes. IC50 values for EAAT2 and EAAT3 inhibition in cells were 2.2 and 24.5 μM, respectively, while EAAT1 activity was inhibited by 50% at 100 μM (IC50 values determined in oocytes were 1.3 μM (EAAT2), 52.5 μM (EAAT3) and 125.9 μM (EAAT1)). Application of WAY‐855 to EAAT‐expressing oocytes failed to induce a transporter current, and the compound failed to exchange with accumulated [3H]D‐aspartate in synaptosomes consistent with a nonsubstrate inhibitor. WAY‐855 inhibited D‐aspartate uptake into cortical synaptosomes by a competitive mechanism, and with similar potency to that observed for the cloned EAAT2. WAY‐855 failed to agonise or antagonise ionotropic glutamate receptors in cultured hippocampal neurones, or the human metabotropic glutamate receptor subtype 4 expressed in a stable cell line. WAY‐855 represents a novel structure in glutamate transporter pharmacology, and exploration of this structure might provide insights into the discrimination between EAAT2 and other EAAT subtypes.

Identification of 3-sulfonylindazole derivatives as potent and selective 5-HT6 antagonists

As part of our efforts to develop agents for cognitive enhancement, we have been focused on the 5-HT(6) receptor in order to identify potent and selective ligands for this purpose. Herein we report the identification of a novel series of 3-sulfonylindazole derivatives with acyclic amino side chains as potent and selective 5-HT(6) antagonists. The synthesis and detailed SAR of this class of compounds are reported.

Convenient synthesis of functionalized terphenyls

A convenient synthetic methodology amenable for rapid synthesis of differentially functionalized terphenyls is described. Orthogonality requirements for the incorporation of phenoxy acetic acid and carboxamide function have been satisfied by utilization of hydroxyethoxy group as a precursor of the acid. Highly efficient and universal procedures have been developed for acid and amide formation.

Tetrahydrocarbazole-based serotonin reuptake inhibitor/dopamine D2 partial agonists for the potential treatment of schizophrenia.

A 5-fluoro-tetrahydrocarbazole serotonin reuptake inhibitor (SRI) building block was combined with a variety of linkers and dopamine D2 receptor ligands in an attempt to identify potent D2 partial agonist/SRI molecules for treatment of schizophrenia. This approach has the potential to treat a broader range of symptoms compared to existing therapies. Selected compounds in this series demonstrate high affinity for both targets and D2 partial agonism in cell-based and in vivo assays.