Linked Life Data

8784447

Source:http://linkedlifedata.com/resource/pubmed/id/8784447

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
18
pubmed:dateCreated
1996-10-17
pubmed:abstractText
Derivatives of the selective serotonin 5-HT1A receptor agonist (R)-11-hydroxy-10-methylaporphine (2) having various substituents in the C10-position or at the nitrogen have been synthesized from natural morphine or 6-O-acetylcodeine, respectively. The C10-substituents were introduced using efficient Stille or Suzuki cross-coupling reactions. The compounds were evaluated for their affinities to 5-HT1A and dopamine (DA) D1 and D2A receptors in vitro. All compounds tested displayed low (micromolar) affinities to D1 and D2A receptors. In addition, changes in steric bulk and/or electronic properties of the C10-substituent as compared to a C10-methyl group, as well as substitution of the N-methyl group for a hydrogen or a larger N-alkyl group, produced a marked decrease in the affinities to 5-HT1A receptors. Selected compounds that displayed moderate to high affinities to 5-HT1A receptors were evaluated for their ability to stimulate 5-HT1A receptors in vivo. The evaluated compounds behaved as agonists at 5-HT1A receptors, except for the N-propyl analogue of 2, (R)-11-hydroxy-10-methyl-N-propylnoraporphine (23), which displayed weak DA receptor agonism at the doses tested. Hence, the substitution pattern of 2 (a C10-methyl, a C11-hydroxy, and an N-methyl group) appears to be optimal for potent interaction of 10,11-disubstituted (R)-aporphines with 5-HT1A receptors. Modeling of ligand-5-HT1A receptor interactions was performed in an attempt to rationalize the observed affinity data. The binding site model suggests the presence of a "methyl pocket" in the 5-HT1A receptor binding ste. The C11-methoxy-substituted aporphines appear to have a different binding mode compared to 2, implying a different accessibility of these compounds to the "methyl pocket".
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
30
pubmed:volume
39
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3491-502
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed:year
1996
pubmed:articleTitle
10-substituted 11-oxygenated (R)-aporphines: synthesis, pharmacology, and modeling of 5-HT1A receptor interactions.
pubmed:affiliation
Uppsala University, Uppsala Biomedical Centre, Sweden.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't