Improving the affinity and selectivity of a nonpeptide series of cholecystokinin-B/gastrin receptor antagonists based on the dibenzobicyclo[2.2.2]octane skeleton

J Med Chem. 1995 Oct 13;38(21):4294-302. doi: 10.1021/jm00021a019.

Abstract

We have recently described a novel series of nonpeptidic cholecystokinin-B (CCKB)/gastrin receptor antagonists based on a dibenzobicyclo[2.2.2]octane skeleton. We wish now to report on compounds arising out of our earlier work which have substantially greater affinity as antagonists for the CCKB/gastrin receptor system and which maintain, or improve on, the already high selectivity with respect to CCKA receptors. Thus, cis-7-[[[(1S)-[[3,5-dicarboxy-phenyl)amino]carbonyl]-2- phenylethyl]amino]carbonyl]-8-[[(1-adamantylmethyl)amino]- carbonyl]-2,3:5,6-dibenzobicyclo[2.2.2]octane expressed a pKi of 8.80 in mouse cortical membranes at CCKB/gastrin receptors. The selectivity for these receptors over CCKA receptors was in the order of 1000-fold.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Cerebral Cortex / metabolism
  • Mice
  • Molecular Structure
  • Polycyclic Compounds / chemistry*
  • Receptor, Cholecystokinin A
  • Receptor, Cholecystokinin B
  • Receptors, Cholecystokinin / antagonists & inhibitors*
  • Receptors, Cholecystokinin / metabolism
  • Structure-Activity Relationship

Substances

  • Polycyclic Compounds
  • Receptor, Cholecystokinin A
  • Receptor, Cholecystokinin B
  • Receptors, Cholecystokinin
  • dibenzobicyclo(2.2.2)octane