Linked Life Data

1552497

Source:http://linkedlifedata.com/resource/pubmed/id/1552497

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
1992-4-28
pubmed:abstractText
The synthesis and biochemical evaluation of a series of spirofused indole oxazoline 5-HT3 antagonists is described in which the oxazoline ring acts as a bioisosteric replacement for esters and amides. The effect of substitution about the indole ring has shown the steric limitations of the aromatic binding site. Incorporation of a variety of azabicyclic systems within the rigid spirofused framework has allowed the definition of a binding model which incorporates a number of known antagonists and agonists. In this model steric constraints limit substitution around the indole ring although there is some bulk tolerance at the 1- and 2-positions. The importance of constraining the basic nitrogen within an azabicyclic system is underlined by comparison with the monocyclic piperidine. The highest affinity was observed for those compounds in which the basic nitrogen occupies a bridgehead position, the most potent analogue in this group being the azabicyclic [3.3.1] system (pIC50 = 8.95), suggesting lipophilic interactions may play a role in increasing affinity. A suggested model for agonist binding is included in which the basic nitrogens are superimposed and the 5-hydroxyl group of 5-HT is superimposed on the H-bond-accepting atom of the heterocyclic linking group.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
20
pubmed:volume
35
pubmed:owner
NLM
pubmed:authorsComplete
N
pubmed:pagination
1019-31
pubmed:dateRevised
2003-11-14
pubmed:meshHeading
pubmed:year
1992
pubmed:articleTitle
Novel 5-HT3 antagonists: indol-3-ylspiro(azabicycloalkane-3,5'(4'H)-oxazoles).
pubmed:affiliation
Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, U.K.
pubmed:publicationType
Journal Article