Linopirdine
Template:Short description Template:Drugbox
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
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
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