Agonists and antagonists for P2 receptors.
Novartis Found Symp
; 276: 58-68; discussion 68-72, 107-12, 275-81, 2006.
Article
in En
| MEDLINE
| ID: mdl-16805423
ABSTRACT
Recent work has identified nucleotide agonists selective for P2Y1, P2Y2 and P2Y6 receptors and nucleotide antagonists selective for P2Y1, P2Y12 and P2X1 receptors. Selective non-nucleotide antagonists have been reported for P2Y1, P2Y2, P2Y6, P2Y12, P2Y13, P2X(2/3)/P2X3 and P2X7 receptors. For example, the dinucleotide INS 37217 (Up4dC) potently activates the P2Y2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X(2/3)/P2X3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformationally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y1,2,4,11 receptors, there is a preference for the North conformation as indicated with (N)-methanocarba analogues. The P2Y1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC50 of 0.95 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC50) of 0.4nM at the P2Y1 receptor, with >10000-fold selectivity in comparison to P2Y12 and P2Y13 receptors. At P2Y6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Purinergic P2 Receptor Agonists
/
Purinergic P2 Receptor Antagonists
/
Nucleotides
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Novartis Found Symp
Journal subject:
MEDICINA
Year:
2006
Type:
Article
Affiliation country:
United States