Linopirdine

Linopirdine
Clinical data
ATC code
Identifiers
  • 1-phenyl-3,3-bis(pyridin-4-ylmethyl)-1,3-dihydro-2H-indol-2-one
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC26H21N3O
Molar mass391.474 g·mol−1
3D model (JSmol)
  • O=C2N(c1ccccc1C2(Cc3ccncc3)Cc4ccncc4)c5ccccc5
  • InChI=1S/C26H21N3O/c30-25-26(18-20-10-14-27-15-11-20,19-21-12-16-28-17-13-21)23-8-4-5-9-24(23)29(25)22-6-2-1-3-7-22/h1-17H,18-19H2 checkY
  • Key:YEJCDKJIEMIWRQ-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Linopirdine is a putative cognition-enhancing drug with a novel mechanism of action. Linopirdine blocks the KCNQ2\3 heteromer M current with an IC50 of 2.4 micromolar[1] disinhibiting acetylcholine release, and increasing hippocampal CA3-schaffer collateral mediated glutamate release onto CA1 pyramidal neurons.[2] In a murine model linopirdine is able to nearly completely reverse the senescence-related decline in cortical c-FOS, an effect which is blocked by atropine and MK-801, suggesting Linopirdine can compensate for the age related decline in acetylcholine release.[3] Linopirdine also blocks homomeric KCNQ1 and KCNQ4 voltage gated potassium channels which contribute to vascular tone with substantially less selectivity than KCNQ2/3.[1] Linopirdine also acts as a glycine receptor antagonist in concentrations typical for Kv7 studies in the brain.[4]

  1. ^ a b Schnee ME, Brown BS (August 1998). "Selectivity of linopirdine (DuP 996), a neurotransmitter release enhancer, in blocking voltage-dependent and calcium-activated potassium currents in hippocampal neurons". The Journal of Pharmacology and Experimental Therapeutics. 286 (2): 709–717. PMID 9694925.
  2. ^ Sun J, Kapur J (August 2012). "M-type potassium channels modulate Schaffer collateral-CA1 glutamatergic synaptic transmission". The Journal of Physiology. 590 (16): 3953–3964. doi:10.1113/jphysiol.2012.235820. PMC 3476642. PMID 22674722.
  3. ^ Dent GW, Rule BL, Zhan Y, Grzanna R (2001). "The acetylcholine release enhancer linopirdine induces Fos in neocortex of aged rats". Neurobiology of Aging. 22 (3): 485–494. doi:10.1016/s0197-4580(00)00252-9. PMID 11378256. S2CID 45164.
  4. ^ Lu HW, Romero GE, Apostolides PF, Huang H, Trussell LO (2022-03-02). "Kv7 channel antagonists block glycine receptors". bioRxiv. doi:10.1101/2022.03.02.482705. S2CID 247231429.