Linopirdine

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]

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)

Synthesis
Linopirdine synthesis:[5] ~90%:[6] Patents ~90%:[7][8]

The amide formation between diphenylamine (1) and oxalyl chloride [79-37-8] gives intermediate, CID:11594101 (2). Haworth type intramolecular cyclization of the acid chloride occurs on heating to afford 1-phenylisatin [723-89-7] (3). The reaction with 4-picoline (4) under PTC with a Quat. salt afforded the carbinol, CID:10358387 (5). Dehydration of the alcohol using acetic anhydride gives [33546-08-6] (6). The reduction of the olefin then afforded the indolone, CID:10470081 (7). The 3 position is now activated by the adjacent benzene ring on one side and the carbonyl group on the other. Alkylation with 4-picolylchloride [10445-91-7] (8) proceeds with hydroxide as the base to afford Linopirdine (9).

References
  1. 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.
  5. Bryant III WM, Huhn GF, Jensen JH, Pierce ME, Stammbach C (1993). "A Large Scale Preparation of the Cognitive Enhancer Linopirdine". Synthetic Communications. 23 (11): 1617–1625. doi:10.1080/00397919308011258.
  6. Yadav JS, Reddy BV (2003). "Microwave-Assisted Rapid Synthesis of Neurotransmitter Release Enhancer Linopiridine and Its New Analogues". Synthetic Communications. 33 (18): 3115–3121. doi:10.1081/SCC-120023425. S2CID 98146660.
  7. US 4806651, Bryant III WM, Huhn GF, issued 1989, assigned to E.I. Du Pont De Nemours and Company
  8. US 5173489, Earl RA, Myers MJ, Nickolson VJ, issued 1992, assigned to The Dupont Merck Pharmaceutical Co.
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