Linked Life Data

21422162

Source:http://linkedlifedata.com/resource/pubmed/id/21422162

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2011-5-17
pubmed:abstractText
The 5-hydroxytryptamine (5-HT) 1E receptor is highly expressed in the human frontal cortex and hippocampus, and this distribution suggests the function of 5-HT(1E) receptors might be linked to memory. To test this hypothesis, behavioral experiments are needed. Because rats and mice lack a 5-HT(1E) receptor gene, knockout strategies cannot be used to elucidate this receptor's functions. Thus, selective pharmacological tools must be developed. The tryptamine-related agonist BRL54443 [5-hydroxy-3-(1-methylpiperidin-4-yl)-1H-indole] is one of the few agents that binds 5-HT(1E) receptors with high affinity and some selectively; unfortunately, it binds equally well to 5-HT(1F) receptors (K(i) ? 1 nM). The differences between tryptamine binding requirements of these two receptor populations have never been extensively explored; this must be done to guide the design of analogs with greater selectivity for 5-HT(1E) receptors versus 5-HT(1F) receptors. Previously, we determined the receptor binding affinities of a large series of tryptamine analogs at the 5-HT(1E) receptor; we now examine the affinities of this same series of compounds at 5-HT(1F) receptors. The affinities of these compounds at 5-HT(1E) and 5-HT(1F) receptors were found to be highly correlated (r = 0.81). All high-affinity compounds were full agonists at both receptor populations. We identified 5-N-butyryloxy-N,N-dimethyltryptamine as a novel 5-HT(1F) receptor agonist with >60-fold selectivity versus 5-HT(1E) receptors. There is significant overlap between 5-HT(1E) and 5-HT(1F) receptor orthosteric binding properties; thus, identification of 5-HT(1E)-selective orthosteric ligands will be difficult. The insights generated from this study will inform future drug development and molecular modeling studies for both 5-HT(1E) and 5-HT(1F) receptors.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1521-0103
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
337
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
860-7
pubmed:meshHeading
pubmed-meshheading:21422162-Animals, pubmed-meshheading:21422162-Antihypertensive Agents, pubmed-meshheading:21422162-CHO Cells, pubmed-meshheading:21422162-Cricetinae, pubmed-meshheading:21422162-Cricetulus, pubmed-meshheading:21422162-Drug Design, pubmed-meshheading:21422162-Forskolin, pubmed-meshheading:21422162-Hippocampus, pubmed-meshheading:21422162-Humans, pubmed-meshheading:21422162-Molecular Targeted Therapy, pubmed-meshheading:21422162-Pargyline, pubmed-meshheading:21422162-Protein Binding, pubmed-meshheading:21422162-Radioligand Assay, pubmed-meshheading:21422162-Receptors, Serotonin, pubmed-meshheading:21422162-Serotonin, pubmed-meshheading:21422162-Serotonin Receptor Agonists, pubmed-meshheading:21422162-Structure-Activity Relationship, pubmed-meshheading:21422162-Tryptamines
pubmed:year
2011
pubmed:articleTitle
Toward selective drug development for the human 5-hydroxytryptamine 1E receptor: a comparison of 5-hydroxytryptamine 1E and 1F receptor structure-affinity relationships.
pubmed:affiliation
Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural