Linopirdine

Linopirdine

Clinical data
ATC code	N06BX09 ( WHO )
Identifiers
IUPAC name 1-phenyl-3,3-bis(pyridin-4-ylmethyl)-1,3-dihydro-2H-indol-2-one
CAS Number	105431-72-9  N
PubChem CID	3932
IUPHAR/BPS	2599
ChemSpider	3795  Y
UNII	I5TB3NZ94T
KEGG	D04741  Y
ChEMBL	ChEMBL319111  Y
CompTox Dashboard (EPA)	DTXSID6045163
Chemical and physical data
Formula	C26H21N3O
Molar mass	391.474 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C2N(c1ccccc1C2(Cc3ccncc3)Cc4ccncc4)c5ccccc5
InChI 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 Y Key:YEJCDKJIEMIWRQ-UHFFFAOYSA-N Y
NY  (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]

Synthesis

Linopirdine synthesis: ~90%: Patents ~90%:

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.