Linopirdine: Difference between revisions
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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 2.4nM<ref name="pmid9694925">{{Cite pmid|9694925}}</ref> disinhibiting acetylcholine release, and increasing hippocampal CA3-schaffer collateral mediated glutamate release onto CA1 pyramidal neurons.<ref name="pmid22674722">{{Cite pmid|22674722}}</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 pmid|11378256}}</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">{{Cite pmid|9694925}}</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 2.4nM<ref name="pmid9694925">{{Cite pmid|9694925}}</ref> disinhibiting acetylcholine release, and increasing hippocampal CA3-schaffer collateral mediated glutamate release onto CA1 pyramidal neurons.<ref name="pmid22674722">{{Cite pmid|22674722}}</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 pmid|11378256}}</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">{{Cite pmid|9694925}}</ref> |
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==Synthesis== |
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[[File:Linopirdine synthesis.png|thumb|center|700px|Linopirdine synthesis:<ref>{{Cite doi|10.1080/00397919308011258}}</ref>]] |
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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 (). Reaction of that product with [[4-picoline]] under [[phase-transfer catalysis|phase-transfer]] conditions catalyzed by a [[quaternary salt]] affords the carbinol () 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]] (). 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. |
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==See also== |
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* [[Besipirdine]] |
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* [[Sibopirdine]] |
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==References== |
==References== |
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Revision as of 15:08, 26 January 2015
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| Formula | C26H21N3O |
| Molar mass | 391.465 g/mol g·mol−1 |
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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 2.4nM[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]
References
- ^ a b Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 9694925, please use {{cite journal}} with
|pmid=9694925instead. - ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 22674722, please use {{cite journal}} with
|pmid=22674722instead. - ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 11378256, please use {{cite journal}} with
|pmid=11378256instead.
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