Synthesis and evaluation of tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease
Seventeen polycyclic compounds related to tacrine and huperzine A have been prepared as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. The conjunctive pharmacomodulation of huperzine A (carbobicyclic substructure) and tacrine (4-aminoquinoline substructure) led to compound 7j...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 1998-04, Vol.6 (4), p.427-440 |
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| creator | Badia, A Baños, J E Camps, P Contreras, J Görbig, D M Muñoz-Torrero, D Simón, M Vivas, N M |
| description | Seventeen polycyclic compounds related to tacrine and huperzine A have been prepared as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. The conjunctive pharmacomodulation of huperzine A (carbobicyclic substructure) and tacrine (4-aminoquinoline substructure) led to compound 7jy, 2.5 times less active than tacrine as AChE inhibitor, but much more active than its (Z)-stereoisomer (7iy). Derivatives 7dy and 7ey, lacking the ethylidene substituent, showed to be more active than tacrine. Many other structural modifications of 7jy led to less active compounds. Compounds 7dy and 7ey also showed to be much more active than tacrine in reversing the partial neuromuscular blockade induced by d-tubocurarine. |
| doi_str_mv | 10.1016/S0968-0896(98)00015-7 |
| format | Article |
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The conjunctive pharmacomodulation of huperzine A (carbobicyclic substructure) and tacrine (4-aminoquinoline substructure) led to compound 7jy, 2.5 times less active than tacrine as AChE inhibitor, but much more active than its (Z)-stereoisomer (7iy). Derivatives 7dy and 7ey, lacking the ethylidene substituent, showed to be more active than tacrine. Many other structural modifications of 7jy led to less active compounds. 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Compounds 7dy and 7ey also showed to be much more active than tacrine in reversing the partial neuromuscular blockade induced by d-tubocurarine.</description><subject>Acetylcholinesterase - metabolism</subject><subject>Alkaloids</subject><subject>Alzheimer Disease - drug therapy</subject><subject>Animals</subject><subject>Cattle</subject><subject>Cholinesterase Inhibitors - chemical synthesis</subject><subject>Cholinesterase Inhibitors - pharmacology</subject><subject>Cholinesterase Inhibitors - therapeutic use</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Male</subject><subject>Neuromuscular Junction - drug effects</subject><subject>Neuroprotective Agents - chemistry</subject><subject>Neuroprotective Agents - pharmacology</subject><subject>Neuroprotective Agents - therapeutic use</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Sesquiterpenes - chemistry</subject><subject>Sesquiterpenes - pharmacology</subject><subject>Spectrophotometry, Infrared</subject><subject>Tacrine - analogs & derivatives</subject><subject>Tacrine - pharmacology</subject><subject>Tacrine - therapeutic use</subject><issn>0968-0896</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kctq3TAQhrVoSdO0jxDQqpeFU8kXXZaH0Esg0EXatRhJY6xiW6eSXDh5k75t5eYQEIyY_5t_hH5Crjm74YyLTw9MC9UwpcUHrT4yxvjQyBfk8rn9irzO-VcV2l7zC3KhBy25kpfk78NpLRPmkCmsnuIfmDcoIa40jrSAS2HFZtqOmB7rjR7odLIp-ErX47CcZjfFuUq5YIKMNKxTsKHElHeHYyy4lgBz7VegUnSMidaNtCSEslR15w7z44RhwfQ-Ux8yVqc35OUIc8a353pFfn75_OP2W3P__evd7eG-cR3rS2MBbKuZ6rWyIAQ4Cx066xTvBiHQOe-8t1p2uuP9KHw7DjCK3stWtuABuyvy7sn3mOLvrb7QLCE7nGdYMW7ZSK1UL9u-gsMT6FLMOeFojikskE6GM7PHYP7HYPb_NrrWPQYj69z1ecFmF_TPU-cMun86oItl</recordid><startdate>199804</startdate><enddate>199804</enddate><creator>Badia, A</creator><creator>Baños, J E</creator><creator>Camps, P</creator><creator>Contreras, J</creator><creator>Görbig, D M</creator><creator>Muñoz-Torrero, D</creator><creator>Simón, M</creator><creator>Vivas, N M</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>199804</creationdate><title>Synthesis and evaluation of tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease</title><author>Badia, A ; Baños, J E ; Camps, P ; Contreras, J ; Görbig, D M ; Muñoz-Torrero, D ; Simón, M ; Vivas, N M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c304t-baab2908498ba66acba3ecbc813566eccdcddb9739314f6d2f5af64d7272adae3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Acetylcholinesterase - metabolism</topic><topic>Alkaloids</topic><topic>Alzheimer Disease - drug therapy</topic><topic>Animals</topic><topic>Cattle</topic><topic>Cholinesterase Inhibitors - chemical synthesis</topic><topic>Cholinesterase Inhibitors - pharmacology</topic><topic>Cholinesterase Inhibitors - therapeutic use</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Male</topic><topic>Neuromuscular Junction - drug effects</topic><topic>Neuroprotective Agents - chemistry</topic><topic>Neuroprotective Agents - pharmacology</topic><topic>Neuroprotective Agents - therapeutic use</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Sesquiterpenes - chemistry</topic><topic>Sesquiterpenes - pharmacology</topic><topic>Spectrophotometry, Infrared</topic><topic>Tacrine - analogs & derivatives</topic><topic>Tacrine - pharmacology</topic><topic>Tacrine - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Badia, A</creatorcontrib><creatorcontrib>Baños, J E</creatorcontrib><creatorcontrib>Camps, P</creatorcontrib><creatorcontrib>Contreras, J</creatorcontrib><creatorcontrib>Görbig, D M</creatorcontrib><creatorcontrib>Muñoz-Torrero, D</creatorcontrib><creatorcontrib>Simón, M</creatorcontrib><creatorcontrib>Vivas, N M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Badia, A</au><au>Baños, J E</au><au>Camps, P</au><au>Contreras, J</au><au>Görbig, D M</au><au>Muñoz-Torrero, D</au><au>Simón, M</au><au>Vivas, N M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and evaluation of tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>1998-04</date><risdate>1998</risdate><volume>6</volume><issue>4</issue><spage>427</spage><epage>440</epage><pages>427-440</pages><issn>0968-0896</issn><abstract>Seventeen polycyclic compounds related to tacrine and huperzine A have been prepared as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. 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| ispartof | Bioorganic & medicinal chemistry, 1998-04, Vol.6 (4), p.427-440 |
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| subjects | Acetylcholinesterase - metabolism Alkaloids Alzheimer Disease - drug therapy Animals Cattle Cholinesterase Inhibitors - chemical synthesis Cholinesterase Inhibitors - pharmacology Cholinesterase Inhibitors - therapeutic use Magnetic Resonance Spectroscopy Male Neuromuscular Junction - drug effects Neuroprotective Agents - chemistry Neuroprotective Agents - pharmacology Neuroprotective Agents - therapeutic use Rats Rats, Sprague-Dawley Sesquiterpenes - chemistry Sesquiterpenes - pharmacology Spectrophotometry, Infrared Tacrine - analogs & derivatives Tacrine - pharmacology Tacrine - therapeutic use |
| title | Synthesis and evaluation of tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease |
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