Linked Life Data

10737741

Source:http://linkedlifedata.com/resource/pubmed/id/10737741

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2000-4-13
pubmed:abstractText
In a continuing effort to further characterize the role of the dopamine transporter in the pharmacological effects of cocaine, a series of chiral and achiral N-substituted analogues of 3alpha-[bis(4'-fluorophenyl)methoxy]tropane (5) has been prepared as potential selective dopamine transporter ligands. These novel compounds displaced [(3)H]WIN 35,428 binding from the dopamine transporter in rat caudate putamen with K(i) values ranging from 13. 9 to 477 nM. Previously, it was reported that 5 demonstrated a significantly higher affinity for the dopamine transporter than the parent drug, 3alpha-(diphenylmethoxy)tropane (3; benztropine). However, 5 remained nonselective over muscarinic m(1) receptors (dopamine transporter, K(i) = 11.8 nM; m(1), K(i) = 11.6 nM) which could potentially confound the interpretation of behavioral data, for this compound and other members of this series. Thus, significant effort has been directed toward developing analogues that retain high affinity at the dopamine transporter but have decreased affinity at muscarinic sites. Recently, it was discovered that by replacing the N-methyl group of 5 with the phenyl-n-butyl substituent (6) retention of high binding affinity at the dopamine transporter (K(i) = 8.51 nM) while decreasing affinity at muscarinic receptors (K(i) = 576 nM) was achieved, resulting in 68-fold selectivity. In the present series, a further improvement in the selectivity for the dopamine transporter was accomplished, with the chiral analogue (S)-N-(2-amino-3-methyl-n-butyl)-3alpha-[bis(4'-fluorophenyl)metho xy] tropane (10b) showing a 136-fold selectivity for the dopamine transporter versus muscarinic m(1) receptors (K(i) = 29.5 nM versus K(i) = 4020 nM, respectively). In addition, a comparative molecular field analysis (CoMFA) model was derived to correlate the binding affinities of all the N-substituted 3alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues that we have prepared with their 3D-structural features. The best model (q(2) = 0. 746) was used to accurately predict binding affinities of compounds in the training set and in a test set. The CoMFA coefficient contour plot for this model, which provides a visual representation of the chemical environment of the binding domain of the dopamine transporter, can now be used to design and/or predict the binding affinities of novel drugs within this class of dopamine uptake inhibitors.
pubmed:grant
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
23
pubmed:volume
43
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1085-93
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:10737741-Animals, pubmed-meshheading:10737741-Binding, Competitive, pubmed-meshheading:10737741-Carrier Proteins, pubmed-meshheading:10737741-Dopamine, pubmed-meshheading:10737741-Dopamine Agents, pubmed-meshheading:10737741-Dopamine Plasma Membrane Transport Proteins, pubmed-meshheading:10737741-Ligands, pubmed-meshheading:10737741-Male, pubmed-meshheading:10737741-Membrane Glycoproteins, pubmed-meshheading:10737741-Membrane Transport Proteins, pubmed-meshheading:10737741-Models, Molecular, pubmed-meshheading:10737741-Nerve Tissue Proteins, pubmed-meshheading:10737741-Putamen, pubmed-meshheading:10737741-Rats, pubmed-meshheading:10737741-Rats, Sprague-Dawley, pubmed-meshheading:10737741-Receptor, Muscarinic M1, pubmed-meshheading:10737741-Receptors, Muscarinic, pubmed-meshheading:10737741-Stereoisomerism, pubmed-meshheading:10737741-Structure-Activity Relationship, pubmed-meshheading:10737741-Tropanes
pubmed:year
2000
pubmed:articleTitle
Highly selective chiral N-substituted 3alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues for the dopamine transporter: synthesis and comparative molecular field analysis.
pubmed:affiliation
Medicinal Chemistry and Psychobiology Sections, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S.