Krintel, Christian’s team published research in Biophysical Journal in 110 | CAS: 1204572-55-3

Krintel, Christian published the artcileEnthalpy-entropy compensation in the binding of modulators at ionotropic glutamate receptor GluA2, Category: thiazole, the publication is Biophysical Journal (2016), 110(11), 2397-2406, database is CAplus and MEDLINE.

The 1,2,4-benzothiadiazine 1,1-dioxide type of pos. allosteric modulators of the ionotropic glutamate receptor A2 (GluA2) are promising lead compounds for the treatment of cognitive disorders, e.g., Alzheimer’s disease. The modulators bind in a cleft formed by the interface of 2 neighboring ligand binding domains and act by stabilizing the agonist-bound open-channel conformation. The driving forces behind the binding of these modulators can be significantly altered with only minor substitutions to the parent mols. Here, the authors show that changing the 7-F substituent of modulators BPAM 97 (I) and BPAM 344 (II) into a OH group (BPAM 557 (III) and BPAM 521 (IV), resp.), leads to a more favorable binding enthalpy (ΔH, kcal/mol) from -4.9 for I and -7.5 for II to -6.2 for III and -14.5 for IV, but also a less favorable binding entropy (-TΔS, kcal/mol) from -2.3 for I and -1.3 for II to -0.5 for III and 4.8 for IV. Thus, the dissociation constants (K_d, μM) of III (11.2) and IV (0.16) were similar to those of I (5.6) and II (0.35). Functionally, III and IV potentiated responses of 10 μM L-glutamate at homomeric rat GluA2(Q)_i receptors with EC₅₀ values of 67.3 and 2.45 μM, resp. The binding mode of IV was examined with x-ray crystallog., showing that the only change compared to that of earlier compounds was the orientation of Ser-497 pointing toward the OH group of IV. The favorable enthalpy could be explained by the formation of a H-bond from the side-chain OH group of Ser-497 to the OH group of IV, whereas the unfavorable entropy might be due to desolvation effects combined with a conformational restriction of Ser-497 and IV. In summary, this study shows a remarkable example of enthalpy-entropy compensation in drug development accompanied with a likely explanation of the underlying structural mechanism.

Biophysical Journal published new progress about 1204572-55-3. 1204572-55-3 belongs to thiazole, auxiliary class Neuronal Signaling,GluR, name is 4-Cyclopropyl-7-fluoro-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide, and the molecular formula is C10H11FN2O2S, Category: thiazole.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/thiazole,
Thiazole | chemical compound | Britannica