Synthesis and X-ray Crystallographic Analysis of Quinazolinone cholecystokinin/gastrin Receptor Ligands

J Med Chem. 1992 Jul 10;35(14):2534-42. doi: 10.1021/jm00092a003.

Abstract

Compounds exemplified by 2-[2-(5-bromo-1H-indol-3-yl)ethyl]-3-[3-(1- methylethoxy)phenyl]-4(3H)-quinazolinone (3, IC50 = 0.0093 microM using mouse brain membranes) represent a structurally novel series of non-peptide cholecystokinin B receptor ligands. Since asperlicin, a selective CCK-A receptor antagonist, may be regarded as a conformationally constrained 2-substituted-3-phenyl-4(3H)-quinazolinone, the progenitor of compound 3 (compound 2, 2-[2-(1H-indol-3-yl)ethyl]-3-phenyl-4(3H)- quinazolinone) might therefore represent a conformationally flexible pharmacophore of the natural product. To probe possible conformational preferences for this class of receptor ligands, in particular the spatial relationship between the indole and quinazolinone rings, we prepared a series of analogues with methyl substituents on the ethylene bridge as well as congeners with different linkers. The X-ray crystal structure conformation for compound 22 (2-[2-(1H-indol-3-yl)ethyl]-3-]-3-(1-methylethoxy) phenyl]-4(3H)-quinazolinone, IC50 = 0.026 microM) is extended with the two heteroaromatic rings adopting an antiperiplanar arrangement around the central sigma bond of the ethane linker, whereas the solid-state conformation for a less active analogue 19 (2-[2-(1H-indol-3-yl)-1-methylethyl]-3-[3-(1- methylethoxy)phenyl]-4(3H)-quinazolinone, IC50 = 9.1 microM) is folded with the two heteroaromatic systems adopting a synclinal orientation. However, MM2 force field calculations (MacroModel, v 3.0) suggest that the energy difference between the folded and extended conformation is small. Thus, other factors such as unfavorable steric interactions may account for the difference in receptor affinity. For derivatives with one to three methylene units separating the indole and quinazolinone rings, maximal receptor binding activity was found when the distance separating the two heteroaromatic systems is defined by an ethyl group. Introducing unsaturation into the ethylene bridge of compound 3 limited the conformational flexibility of the molecule and decreased its receptor affinity greater than 2 orders of magnitude.

MeSH terms

  • Animals
  • Brain / metabolism
  • Computer Simulation
  • Ligands
  • Mice
  • Models, Molecular
  • Quinazolines / chemical synthesis*
  • Quinazolines / metabolism
  • Quinazolines / pharmacology
  • Receptors, Cholecystokinin / metabolism*
  • Structure-Activity Relationship
  • X-Ray Diffraction

Substances

  • Ligands
  • Quinazolines
  • Receptors, Cholecystokinin