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Linopirdine

Chemical compound

Linopirdine

Chemical compound

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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.

Synthesis

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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

References

  1. (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.
  2. (August 2012). "M-type potassium channels modulate Schaffer collateral-CA1 glutamatergic synaptic transmission". The Journal of Physiology.
  3. (2001). "The acetylcholine release enhancer linopirdine induces Fos in neocortex of aged rats". Neurobiology of Aging.
  4. (2022-03-02). "Kv7 channel antagonists block glycine receptors".
  5. (1993). "A Large Scale Preparation of the Cognitive Enhancer Linopirdine". Synthetic Communications.
  6. (2003). "Microwave-Assisted Rapid Synthesis of Neurotransmitter Release Enhancer Linopiridine and Its New Analogues". Synthetic Communications.
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  8. {{cite patent
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4-pyridyl-compounds nootropics indolines lactams potassium-channel-blockers oxindoles
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