Ifenprodil

4-[1-hydroxy-2-[4-(phenylmethyl)-1-piperidinyl]propyl]phenol is a member of piperidines.|N-methyl-D-aspartate (NMDA) receptors (NMDARs) are members of the ionotropic glutamate receptor family, with key roles in brain development and neurological function. 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. 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. 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. Although ifenprodil has received considerable interest in its potential neuromodulatory activities in psychiatric conditions, including dependency and depression, it has also been shown to have an immunomodulatory effect. 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. Ifenprodil is being investigated for its potential utility in treating COVID-19 in an ongoing phase 2b/3 clinical trial (NCT04382924).|Ifenprodil is an orally bioavailable, N-methyl-D-aspartate (NMDA) receptor antagonist, with potential central nervous system (CNS) stimulating, neuroprotective, anti-inflammatory and anti-fibrotic activities. Upon administration, ifenprodil targets, binds to and inhibits glutamanergic NMDA receptors (NMDARs), specifically the glycine-binding NMDA receptor subunit 1 (GluN1) and 2 (glutamate-binding NMDA receptor subunit 2; NMDA-type subunit 2B; GluN2B), thereby preventing NMDAR signaling. This inhibits neuronal excitotoxicity, and thereby potentially enhancing cognitive function. Additionally, ifenprodil inhibits G protein-coupled inwardly-rectifying potassium (GIRK) channels, and interacts with alpha1 adrenergic, serotonin, and activates sigma receptors. Ifenprodil exerts its anti-inflammatory effect through its effect on NMDA and possibly sigma-1 receptors. Although the exact mechanism has not fully been elucidated, this agent reduces the infiltration of neutrophils and T-cells into the lungs and prevents the release of pro-inflammatory cytokines. This may result in the reduction of the lung inflammatory response, inhibit fibrosis in the lungs and may reduce the severity of cough. NMDA receptors are multimeric ionotropic glutamate receptors composed of four subunits and are expressed on various cells and organs, such as in the brain, lungs, and on T-cells and neutrophils.

vasodilator

Molecular Weight:325.4
XLogP3:3.9
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:5
Exact Mass:325.204179104
Monoisotopic Mass:325.204179104
Topological Polar Surface Area:43.7
Heavy Atom Count:24
Complexity:353
Undefined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes