8cc7

From Proteopedia

Mouse serotonin 5-HT3A receptor in complex with PZ-1939

Structural highlights

8cc7 is a 5 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

5HT3A_MOUSE This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor is a ligand-gated ion channel, which when activated causes fast, depolarizing responses in neurons. It is a cation-specific, but otherwise relatively nonselective, ion channel.

Publication Abstract from PubMed

The multifactorial origin and neurochemistry of Alzheimer's disease (AD) call for the development of multitarget treatment strategies. We report a first-in-class triple acting compound that targets serotonin type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B) as an approach for treating AD. The key structural features required for MAO-B inhibition and 5-HT(6)R antagonism and interaction with 5-HT(3)R were determined using molecular dynamic simulations and cryo-electron microscopy, respectively. Bioavailable PZ-1922 reversed scopolamine-induced cognitive deficits in the novel object recognition test. Furthermore, it displayed superior pro-cognitive properties compared to intepirdine (a 5-HT(6)R antagonist) in the AD model, which involved intracerebroventricular injection of an oligomeric solution of amyloid-beta peptide (oAbeta) in the T-maze test in rats. PZ-1922, but not intepirdine, restored levels of biomarkers characteristic of the debilitating effects of oAbeta. These data support the potential of a multitarget approach involving the joint modulation of 5-HT(6)R/5-HT(3)R/MAO-B in AD.

Superiority of the Triple-Acting 5-HT(6)R/5-HT(3)R Antagonist and MAO-B Reversible Inhibitor PZ-1922 over 5-HT(6)R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats.,Grychowska K, Lopez-Sanchez U, Vitalis M, Canet G, Satala G, Olejarz-Maciej A, Golebiowska J, Kurczab R, Pietrus W, Kubacka M, Moreau C, Walczak M, Blicharz-Futera K, Bento O, Bantreil X, Subra G, Bojarski AJ, Lamaty F, Becamel C, Zussy C, Chaumont-Dubel S, Popik P, Nury H, Marin P, Givalois L, Zajdel P J Med Chem. 2023 Nov 9;66(21):14928-14947. doi: 10.1021/acs.jmedchem.3c01482. , Epub 2023 Oct 5. PMID:37797083^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Grychowska K, López-Sánchez U, Vitalis M, Canet G, Satała G, Olejarz-Maciej A, Gołębiowska J, Kurczab R, Pietruś W, Kubacka M, Moreau C, Walczak M, Blicharz-Futera K, Bento O, Bantreil X, Subra G, Bojarski AJ, Lamaty F, Becamel C, Zussy C, Chaumont-Dubel S, Popik P, Nury H, Marin P, Givalois L, Zajdel P. Superiority of the Triple-Acting 5-HT(6)R/5-HT(3)R Antagonist and MAO-B Reversible Inhibitor PZ-1922 over 5-HT(6)R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats. J Med Chem. 2023 Nov 9;66(21):14928-14947. PMID:37797083 doi:10.1021/acs.jmedchem.3c01482