Source:http://linkedlifedata.com/resource/pubmed/id/10052975
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
4
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| pubmed:dateCreated |
1999-3-16
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| pubmed:abstractText |
The design, synthesis, and biological evaluation of a novel series of 3-[2-(pyrrolidin-1-yl)ethyl]indoles with excellent selectivity for h5-HT1D (formerly 5-HT1Dalpha) receptors over h5-HT1B (formerly 5-HT1Dbeta) receptors are described. Clinically effective antimigraine drugs such as Sumatriptan show little selectivity between h5-HT1D and h5-HT1B receptors. The differential expression of h5-HT1D and h5-HT1B receptors in neural and vascular tissue prompted an investigation of whether a compound selective for the h5-HT1D subtype would have the same clinical efficacy but with reduced side effects. The pyrrolidine 3b was initially identified as having 9-fold selectivity for h5-HT1D over h5-HT1B receptors. Substitution of the pyrrolidine ring of 3b with methylbenzylamine groups gave compounds with nanomolar affinity for the h5-HT1D receptor and 100-fold selectivity with respect to h5-HT1B receptors. Modification of the indole 5-substituent led to the oxazolidinones 24a,b with up to 163-fold selectivity for the h5-HT1D subtype and improved selectivity over other serotonin receptors. The compounds were shown to be full agonists by measurement of agonist-induced [35S]GTPgammaS binding in CHO cells expressed with h5-HT receptors. This study suggests that the h5-HT1D and h5-HT1B receptors can be differentiated by appropriate substitution of the ligand in the region which binds to the aspartate residue and reveals a large binding pocket in the h5-HT1D receptor domain which is absent for the h5-HT1B receptor. The compounds described herein will be important tools to delineate the role of h5-HT1D receptors in migraine.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/HTR1B protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Indoles,
http://linkedlifedata.com/resource/pubmed/chemical/Oxazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrrolidines,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Serotonin, 5-HT1B,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Serotonin, 5-HT1D,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Serotonin,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Serotonin Receptor Agonists
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| pubmed:status |
MEDLINE
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| pubmed:month |
Feb
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| pubmed:issn |
0022-2623
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| pubmed:author |
pubmed-author:BeerM SMS,
pubmed-author:GuiblinA RAR,
pubmed-author:HealdAA,
pubmed-author:HuntP APA,
pubmed-author:JelleyR ARA,
pubmed-author:MatassaV GVG,
pubmed-author:ReeveA JAJ,
pubmed-author:SohalBB,
pubmed-author:StantonJ AJA,
pubmed-author:SternfeldFF,
pubmed-author:StreetL JLJ,
pubmed-author:WattA PAP
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| pubmed:issnType |
Print
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| pubmed:day |
25
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| pubmed:volume |
42
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
677-90
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| pubmed:dateRevised |
2010-11-18
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| pubmed:meshHeading |
pubmed-meshheading:10052975-Administration, Oral,
pubmed-meshheading:10052975-Animals,
pubmed-meshheading:10052975-Biological Availability,
pubmed-meshheading:10052975-CHO Cells,
pubmed-meshheading:10052975-Cricetinae,
pubmed-meshheading:10052975-Humans,
pubmed-meshheading:10052975-Indoles,
pubmed-meshheading:10052975-Migraine Disorders,
pubmed-meshheading:10052975-Models, Molecular,
pubmed-meshheading:10052975-Oxazoles,
pubmed-meshheading:10052975-Pyrrolidines,
pubmed-meshheading:10052975-Radioligand Assay,
pubmed-meshheading:10052975-Rats,
pubmed-meshheading:10052975-Receptor, Serotonin, 5-HT1B,
pubmed-meshheading:10052975-Receptor, Serotonin, 5-HT1D,
pubmed-meshheading:10052975-Receptors, Serotonin,
pubmed-meshheading:10052975-Recombinant Proteins,
pubmed-meshheading:10052975-Serotonin Receptor Agonists,
pubmed-meshheading:10052975-Structure-Activity Relationship
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| pubmed:year |
1999
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| pubmed:articleTitle |
Synthesis and serotonergic activity of 3-[2-(pyrrolidin-1-yl)ethyl]indoles: potent agonists for the h5-HT1D receptor with high selectivity over the h5-HT1B receptor.
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| pubmed:affiliation |
Chemistry, Biochemistry, and Bioanalytical Departments, Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.
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| pubmed:publicationType |
Journal Article
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