Ifenprodil

N-methyl-D-aspartate (NMDA) receptors (NMDARs) are members of the ionotropic glutamate receptor family, with key roles in brain development and neurological function.A220118, A220128 NMDARs are heterotetramers that typically involve a dimer of dimers of both GluN1 and GluN2A-D subunits, with each subunit itself composed of an N-terminal domain (NTD), a ligand-binding domain (LBD), a transmembrane domain, and a C-terminal cytoplasmic domain. Binding at the LBD of the agonists glycine (or D-serine) to the GluN1 subunits and of glutamate to the GluN2 subunits is a regulatory mechanism for channel activation. In addition, allosteric modulators are known to bind at the NTDs and form another layer of regulation.A220118, A220128 One such allosteric regulator is ifenprodil, which was first shown to bind the NMDARs in the 1990s, and specifically to those NMDARs containing the GluN2B subunit.^A220133 Further studies elucidated that ifenprodil binds strongly at the inter-subunit interface of adjacent GluN1 and GluN2B NTDs, where it acts as a non-competitive antagonist.A220118, A220128

Although ifenprodil has received considerable interest in its potential neuromodulatory activities in psychiatric conditions, including dependency^A220138 and depression,^A220143 it has also been shown to have an immunomodulatory effect.A220143, A196128 In an unbiased screen for compounds capable of reducing cell death induced by infection with the influenza strain H5N1, ifenprodil was found to have a protective effect against H5N1-induced lung damage, in part through its ability to alleviate the H5N1-induced cytokine storm and reduce pulmonary infiltration of neutrophils, natural killer cells, and T cells.^A196128 Ifenprodil is being investigated for its potential utility in treating COVID-19 in an ongoing phase 2b/3 clinical trial (NCT04382924).^L16343