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{{Short description|Chemical compound}}
{{Drugbox
{{Drugbox
| Verifiedfields = changed
| Verifiedfields = changed
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<!--Chemical data-->
<!--Chemical data-->
| C=26 | H=21 | N=3 | O=1
| C=26 | H=21 | N=3 | O=1
| molecular_weight = 391.465 g/mol
| smiles = O=C2N(c1ccccc1C2(Cc3ccncc3)Cc4ccncc4)c5ccccc5
| smiles = O=C2N(c1ccccc1C2(Cc3ccncc3)Cc4ccncc4)c5ccccc5
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
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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<ref name="pmid9694925">{{cite journal | vauthors = Schnee ME, Brown BS | title = Selectivity of linopirdine (DuP 996), a neurotransmitter release enhancer, in blocking voltage-dependent and calcium-activated potassium currents in hippocampal neurons | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 286 | issue = 2 | pages = 709–717 | date = August 1998 | pmid = 9694925 }}</ref> disinhibiting acetylcholine release, and increasing hippocampal CA3-schaffer collateral mediated glutamate release onto CA1 [[pyramidal neurons]].<ref name="pmid22674722">{{cite journal | vauthors = Sun J, Kapur J | title = M-type potassium channels modulate Schaffer collateral-CA1 glutamatergic synaptic transmission | journal = The Journal of Physiology | volume = 590 | issue = 16 | pages = 3953–3964 | date = August 2012 | pmid = 22674722 | pmc = 3476642 | doi = 10.1113/jphysiol.2012.235820 }}</ref> 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.<ref name="pmid11378256">{{cite journal | vauthors = Dent GW, Rule BL, Zhan Y, Grzanna R | title = The acetylcholine release enhancer linopirdine induces Fos in neocortex of aged rats | journal = Neurobiology of Aging | volume = 22 | issue = 3 | pages = 485–494 | year = 2001 | pmid = 11378256 | doi = 10.1016/s0197-4580(00)00252-9 | s2cid = 45164 }}</ref> Linopirdine also blocks homomeric KCNQ1 and KCNQ4 voltage gated potassium channels which contribute to vascular tone with substantially less selectivity than KCNQ2/3.<ref name="pmid9694925"/> Linopirdine also acts as a glycine receptor antagonist in concentrations typical for Kv7 studies in the brain.<ref>{{Cite journal | vauthors = Lu HW, Romero GE, Apostolides PF, Huang H, Trussell LO |date=2022-03-02 |title=Kv7 channel antagonists block glycine receptors | journal = bioRxiv |language=en |doi=10.1101/2022.03.02.482705|s2cid=247231429 }}</ref>
'''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<ref name="pmid9694925">{{Cite journal
| last1 = Schnee | first1 = M. E.
| last2 = Brown | first2 = B. S.
| title = Selectivity of linopirdine (DuP 996), a neurotransmitter release enhancer, in blocking voltage-dependent and calcium-activated potassium currents in hippocampal neurons
| journal = The Journal of Pharmacology and Experimental Therapeutics
| volume = 286
| issue = 2
| pages = 709–717
| year = 1998
| pmid = 9694925
}}</ref> disinhibiting acetylcholine release, and increasing hippocampal CA3-schaffer collateral mediated glutamate release onto CA1 pyramidal neurons.<ref name="pmid22674722">{{Cite journal
| last1 = Sun | first1 = J.
| last2 = Kapur | first2 = J.
| doi = 10.1113/jphysiol.2012.235820
| title = M-type potassium channels modulate Schaffer collateral-CA1 glutamatergic synaptic transmission
| journal = The Journal of Physiology
| volume = 590
| issue = 16
| pages = 3953–3964
| year = 2012
| pmid = 22674722
| pmc =3476642
}}</ref> 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.<ref name="pmid11378256">{{Cite journal
| last1 = Dent | first1 = G. W.
| last2 = Rule | first2 = B. L.
| last3 = Zhan | first3 = Y.
| last4 = Grzanna | first4 = R.
| title = The acetylcholine release enhancer linopirdine induces Fos in neocortex of aged rats
| journal = Neurobiology of Aging
| volume = 22
| issue = 3
| pages = 485–494
| year = 2001
| pmid = 11378256 | doi=10.1016/s0197-4580(00)00252-9
}}</ref> Linopirdine also blocks homomeric KCNQ1 and KCNQ4 voltage gated potassium channels which contribute to vascular tone with substantially less selectivity than KCNQ2/3.<ref name="pmid9694925"/>


==Synthesis==
==Synthesis==
[[File:Linopirdine synthesis.svg|left|thumb|701px|Linopirdine synthesis:<ref>{{Cite journal | vauthors = Bryant III WM, Huhn GF, Jensen JH, Pierce ME, Stammbach C | title = A Large Scale Preparation of the Cognitive Enhancer Linopirdine| journal = Synthetic Communications| volume = 23| issue = 11| pages = 1617–1625| year = 1993 | doi = 10.1080/00397919308011258 }}</ref> ~90%:<ref>{{cite journal | vauthors = Yadav JS, Reddy BV | date = 2003 | title = Microwave-Assisted Rapid Synthesis of Neurotransmitter Release Enhancer Linopiridine and Its New Analogues | journal = Synthetic Communications | volume = 33 | issue = 18 | pages = 3115–3121 | doi = 10.1081/SCC-120023425 | s2cid = 98146660 }}</ref> Patents ~90%:<ref>{{cite patent | inventor = Bryant III WM, Huhn GF | country = US | number = 4806651 | gdate = 1989 | assign1 = E.I. Du Pont De Nemours and Company }}</ref><ref>{{cite patent | inventor = Earl RA, Myers MJ, Nickolson VJ | country = US | number = 5173489 | gdate = 1992 | assign1 = The Dupont Merck Pharmaceutical Co. }}</ref>]]
The synthesis starts with a standard scheme for preparing indoxyls. Thus, acylation of [[diphenylamine]] with [[oxalyl chloride]] leads to the amide. The acid chloride then cyclizes into the ring on heating to afford ('''3'''). Reaction of that product with [[4-picoline]] under [[phase-transfer catalysis|phase-transfer]] conditions catalyzed by a quaternary salt affords the carbinol ('''4''') from addition of the transient anion on the methyl group of the [[picoline]] to the more [[electrophilic]] carbonyl group. The alcohol is then dehydrated by means of [[acetic anhydride]] and the resulting olefin hydrogenated to afford the [[indolone]] ('''5'''). The 3 position is now activated by the adjacent benzene ring on one side and the carbonyl group on the other. Alkylation with α-chloropicoline proceeds with hydroxide as the base to afford Linopirdine ('''6''').
The amide formation between [[diphenylamine]] ('''1''') and [[oxalyl chloride]] [79-37-8] gives intermediate, [https://pubchem.ncbi.nlm.nih.gov/compound/11594101 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, [https://pubchem.ncbi.nlm.nih.gov/compound/10358387 CID:10358387] ('''5'''). Dehydration of the alcohol using [[acetic anhydride]] gives [33546-08-6] ('''6'''). The reduction of the olefin then afforded the [[indolone]], [https://pubchem.ncbi.nlm.nih.gov/compound/10470081 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''').
[[File:Linopirdine synthesis.svg|left|thumb|700px|Linopirdine synthesis:<ref>{{Cite journal | doi = 10.1080/00397919308011258| title = A Large Scale Preparation of the Cognitive Enhancer Linopirdine| journal = Synthetic Communications| volume = 23| issue = 11| pages = 1617–1625| year = 1993| last1 = Bryant | first1 = W. M. | last2 = Huhn | first2 = G. F. | last3 = Jensen | first3 = J. H. | last4 = Pierce | first4 = M. E. | last5 = Stammbach | first5 = C.}}</ref>]]
{{clear}}
{{clear}}
==References==
== References ==
{{Reflist}}
{{Reflist}}


{{Nootropics}}
{{Channel blockers}}
{{Channel blockers}}


[[Category:Pyridines]]
[[Category:4-Pyridyl compounds]]
[[Category:Nootropics]]
[[Category:Nootropics]]
[[Category:Indolines]]
[[Category:Indolines]]
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[[Category:Potassium channel blockers]]
[[Category:Potassium channel blockers]]
[[Category:Oxindoles]]
[[Category:Oxindoles]]

{{nervous-system-drug-stub}}

Latest revision as of 16:58, 30 September 2024

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)

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

[edit]
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

[edit]
  1. ^ a b 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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