Linked Life Data

8691445

Source:http://linkedlifedata.com/resource/pubmed/id/8691445

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
13
pubmed:dateCreated
1996-8-23
pubmed:abstractText
A series of 33 novel, mostly chiral pyrrolo[2,3-d]pyrimidine and pyrimido[4,5-b]indole derivatives has been synthesized and investigated in radioligand binding assays at the high-affinity adenosine receptor (AR) subtypes A1 and A2a. The compounds can be envisaged as adenine and hypoxanthine analogs lacking the nitrogen in the 7-position (7-deazaadenines and 7-deazahypoxanthines). 7-Deazaadenines were much more potent than 7-deazahypoxanthines at AR with A1AR affinities in the low-nanomolar range, extraordinarily high selectivity for the rat brain A1AR versus the A2aAR (several thousandfold), and high stereoselectivity (up to 96-fold). Pyrimido[4,5-b]indoles were more potent A1AR antagonists compared to pyrrolo[2,3-d]pyrimidines. Compound 34a (APEPI) is one of the most potent and most selective nonxanthine A1AR antagonists known to date (Ki = 2.8 nM, > 2000-fold A1-selective). A new class of very potent A1AR antagonists has been identified, namely, 2-phenyl-7-deazaadenines bearing a substituent at the exocyclic amino group (N4-substituted pyrrolo[2,3-d]pyrimidines). (R)-N- (1-Phenylethyl)-4-amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin e (DPEAP, 17a) showed a Ki value of 6.7 nM at A1AR and > 4000-fold A1 selectivity. Different binding modes are postulated for the N4-substituted 4-aminopyrrolo[2,3-d]pyrimidines (e.g., 17a) and the 7-substituted derivatives (e.g., 1a), based on a comparison of steric, electronic, and hydrophobic properties of the two classes of compounds. Water solubility and lipophilicity have been determined for selected compounds. 4-Amino-5,6-dimethyl-2-(3-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (4a) showed the highest water solubility/A1AR affinity ratio of 368 in the present series, over 2000-fold A1 selectivity, and 64-fold stereoselectivity (R > S). Therefore, 4a should be an interesting compound for in vivo evaluation.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
21
pubmed:volume
39
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2482-91
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:8691445-Adenine, pubmed-meshheading:8691445-Animals, pubmed-meshheading:8691445-Cerebral Cortex, pubmed-meshheading:8691445-Computer Graphics, pubmed-meshheading:8691445-Corpus Striatum, pubmed-meshheading:8691445-Hypoxanthines, pubmed-meshheading:8691445-Indoles, pubmed-meshheading:8691445-Magnetic Resonance Spectroscopy, pubmed-meshheading:8691445-Molecular Conformation, pubmed-meshheading:8691445-Molecular Structure, pubmed-meshheading:8691445-Protein Binding, pubmed-meshheading:8691445-Purinergic P1 Receptor Antagonists, pubmed-meshheading:8691445-Pyrimidines, pubmed-meshheading:8691445-Radioligand Assay, pubmed-meshheading:8691445-Rats, pubmed-meshheading:8691445-Receptors, Purinergic P1, pubmed-meshheading:8691445-Solubility, pubmed-meshheading:8691445-Stereoisomerism, pubmed-meshheading:8691445-Structure-Activity Relationship
pubmed:year
1996
pubmed:articleTitle
Chiral pyrrolo[2,3-d]pyrimidine and pyrimido[4,5-b]indole derivatives: structure-activity relationships of potent, highly stereoselective A1-adenosine receptor antagonists.
pubmed:affiliation
Julius-Maximilians-Universität Würzburg, Institut für Pharmazie und Lebensmittelchemie, Pharmazeutische Chemie, Würzburg, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't