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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 disinhibiting acetylcholine release, and increasing hippocampal CA3-schaffer collateral mediated glutamate release onto CA1 pyramidal neurons. 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. Linopirdine also blocks homomeric KCNQ1 and KCNQ4 voltage gated potassium channels which contribute to vascular tone with substantially less selectivity than KCNQ2/3. Linopirdine also acts as a glycine receptor antagonist in concentrations typical for Kv7 studies in the brain.
The amide formation between
CID:11594101
(2). Haworth type intramolecular cyclization of the acid chloride occurs on heating to afford 1-phenylisatin 23-89-7(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 3546-08-6(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 0445-91-7(8) proceeds with hydroxide as the base to afford Linopirdine (9).
Synthesis
The amide formation between diphenylamine
Diphenylamine is an organic compound with the formula (C6H5)2NH. The compound is a derivative of aniline, consisting of an amine bound to two phenyl groups. The compound is a colorless solid, but commercial samples are often yellow due to oxidiz ...
(1) and oxalyl chloride
Oxalyl chloride is an organic chemical compound with the formula (COCl)2. This colorless, sharp-smelling liquid, the diacyl chloride of oxalic acid, is a useful reagent in organic synthesis.
Preparation
Oxalyl chloride was first prepared in 1892 ...
9-37-8gives intermediateCID:11594101
(2). Haworth type intramolecular cyclization of the acid chloride occurs on heating to afford 1-phenylisatin 23-89-7(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 3546-08-6(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 0445-91-7(8) proceeds with hydroxide as the base to afford Linopirdine (9).
References
4-Pyridyl compounds Nootropics Indolines Lactams Potassium channel blockers Oxindoles {{nervous-system-drug-stub