Linked Life Data

16033275

Source:http://linkedlifedata.com/resource/pubmed/id/16033275

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
15
pubmed:dateCreated
2005-7-21
pubmed:abstractText
In our structure-activity relationship study on 3,6-disubstituted pyran derivatives, we have carried out asymmetric synthesis and biological characterization of trisubstituted (2S,4R,5R)-2-benzhydryl-5-benzylaminotetrahydropyran-4-ol and (3S,4R,6S)-6-benzhydryl-4-benzylaminotetrahydropyran-3-ol derivatives and their enantiomers. All synthesized derivatives were tested for their affinities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in inhibiting the uptake of [(3)H]DA, [(3)H]-5-HT, and [(3)H]NE, respectively. Compounds were also tested for their binding affinity at the DAT by their inhibition of [(3)H]WIN 35,428. Biological results indicated that regioselectivity and stereoselectivity played important roles in determining activity for monoamine transporters as only (-)-isomers of 2-benzhydryl-5-benzylaminotetrahydropyran-4-ol derivatives exhibited appreciable potency for the monoamine transporters, in particular for the SERT and NET. Among the active analogues, (-)-9d exhibited potent and selective affinity at the NET (K(i), [(3)H]NE = 4.92 nM; DAT/NET = 91 and SERT/NET = 140). One of the derivatives with p-methoxybenzyl substitution, (-)-9a, was potent at both SERT and NET (K(i), [(3)H]-5-HT = 25.9 and [(3)H]NE = 15.8 nM, respectively). In the active analogue series ((-)-9a-(-)-9e), a cis-relationship between the biphenyl and the amino moiety was maintained for the SERT and NET interactions, as was observed with our earlier 3,6-disubstituted pyran compounds for the DAT interaction. To the best of our knowledge, this current series of compounds represents a novel class of pyran derivatives as blockers for monoamine transporters.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Benzhydryl Compounds, http://linkedlifedata.com/resource/pubmed/chemical/Dopamine Plasma Membrane Transport..., http://linkedlifedata.com/resource/pubmed/chemical/Membrane Glycoproteins, http://linkedlifedata.com/resource/pubmed/chemical/Membrane Transport Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Nerve Tissue Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Norepinephrine Plasma Membrane..., http://linkedlifedata.com/resource/pubmed/chemical/Pyrans, http://linkedlifedata.com/resource/pubmed/chemical/Serotonin Plasma Membrane..., http://linkedlifedata.com/resource/pubmed/chemical/Slc6a2 protein, rat, http://linkedlifedata.com/resource/pubmed/chemical/Slc6a3 protein, rat, http://linkedlifedata.com/resource/pubmed/chemical/Slc6a4 protein, rat, http://linkedlifedata.com/resource/pubmed/chemical/Symporters
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
28
pubmed:volume
48
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4962-71
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Discovery of novel trisubstituted asymmetric derivatives of (2S,4R,5R)-2-benzhydryl-5-benzylaminotetrahydropyran-4-ol, exhibiting high affinity for serotonin and norepinephrine transporters in a stereospecific manner.
pubmed:affiliation
Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan 48202, USA.
pubmed:publicationType
Journal Article, In Vitro, Research Support, U.S. Gov't, P.H.S., Research Support, N.I.H., Extramural