Montelukast - quinoline cysLT1 receptor antagonist In some c...

Montelukast - quinoline cysLT1 receptor antagonist In some cases the introduction of a 7-chlorine atom to the quinoline ring proved beneficial. Correlation of the pKa values of the quinoline nitrogenwith the CysLT1 receptors affinities was reported indicating a possible hydrogen bond interaction between the quinoine nitrogen and the receptor. The quinoline moiety or its equivalents is suggested to mimic the lipophilic region of the CysLT and the acidic groups mimick either the peptide or the eiocosanoid tail of CysLT. The resulting model figure 12 suggests multiple intereactions between the antagonists and the arginine residue. Besides the hydrogen bonds between the acidic residues and the guanidine moiety of arginine, quinoline containing CysLT1 antagonists are shown toe form an additional hydrogen bond beetween the quinoline nitrogen and a guanidine hydrogen atom. This interaction may be an explanation for the importance of the presence and position of a nitrogen atom, as observed for most CysLT1 antagonists of the quinoline class. In addition the antagonists were found to wrap around the arginine and thus "short molecules such as WY48252 are easily fitted in the model. i.e. the variable spacers between the lipophilic and the acidic groups do not post major restrictions to the receptor affinity as long as they are flexible enough to allow the acidic groups to bend back for interaction with the arginine. The incorporation of Montelukast in the model suggests the presence of an additional binding pocket....Since the affinity of LTD4 itself was little affected, arginine residues were suggested to be important for the binding of antagonists but not for LTD4. These results sustained our relucrtance to derive an antagonist model based on structural similarity between the agonists and antagonists. Ming-Qiang Zhang and Mariel Zwaagstra Current Medicinal Chemistry, 1997, Vol. 4, Nov. 4.