Macrocyclic Compounds And Methods Of Making And Using The Same
申请人:Farmer J. Jay
公开号:US20080045585A1
公开(公告)日:2008-02-21
The present invention provides macrocyclic compounds useful as therapeutic agents. More particularly, these compounds are useful as anti-infective, anti-proliferative, anti-inflammatory, and prokinetic agents.
MACROCYCLIC COMPOUNDS AND METHODS OF MAKING AND USING THE SAME
申请人:Farmer Jay J.
公开号:US20120252747A1
公开(公告)日:2012-10-04
The present invention provides macrocyclic compounds useful as therapeutic agents of the formula:
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T, R
1
, R
2
, R
3
, D, E, F, and G are as defined herein. More particularly, these compounds are useful as anti-infective, antiproliferative, anti-inflammatory and prokinetic agents.
Following a recent description of fluorescence resonance energy transfer between enhanced green fluorescent protein (EGFP)-fused human muscarinic M1 receptors and Bodipy-labeled pirenzepine, we synthesized seven fluorescent derivatives of this antagonist in order to further characterize ligand-receptor interactions. These compounds carry Bodipy [558/568], Rhodamine Red-X [560/580], or Fluorolink Cy3 [550/570] fluorophores connected to pirenzepine through various linkers. All molecules reversibly bind with high affinity to M1 receptors (radioligand and energy transfer binding experiments) provided that the linker contains more than six atoms. The energy transfer efficiency exhibits modest variations among ligands, indicating that the distance separating EGFP from the fluorophores remains almost constant. This also supports the notion that the fluorophores may bind to the receptor protein. Kinetic analyses reveal that the dissociation of two Bodipy derivatives (10 or 12 atom long linkers) is sensitive to the presence of the allosteric modulator brucine, while that of all other molecules (15-24 atom long linkers) is not. The data favor the idea that these analogues might interact with both the acetylcholine and the brucine binding domains.