CCK(2) receptor antagonists containing the conformationally constrained phenylalanine derivatives, including the new amino acid Xic

Eur J Med Chem. 2002 May;37(5):379-89. doi: 10.1016/s0223-5234(02)01351-x.

Abstract

The conformationally constrained analogues of phenylalanine, tetrahydroisoquinoline-3-carboxylic acid (Tic), Sic, Hic and Nic, and the new amino acid Xic have been incorporated into a potent and highly selective cholecystokinin-2 (CCK(2)) receptor antagonist (2) in place of the phenylalanine residue, producing compounds 15a-e. High selectivities for CCK(2) over CCK(1) were observed for compounds 15a-e. The in vitro profile of the analogue containing the Nic residue (15d) was identical to that of compound 2, whereas the alternative conformational constraints resulted in a significant loss of affinity. The apparent advantage of Nic in the context of these CCK(2) ligands was subsequently demonstrated to be statistically significant.

MeSH terms

  • Animals
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Gastric Mucosa / metabolism
  • Guinea Pigs
  • Heterocyclic Compounds, 2-Ring / chemical synthesis*
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / pharmacology
  • In Vitro Techniques
  • Isoquinolines / chemistry
  • Ligands
  • Mice
  • Pancreas / drug effects
  • Pancreas / metabolism
  • Phenylalanine / chemistry*
  • Rats
  • Receptor, Cholecystokinin B
  • Receptors, Cholecystokinin / antagonists & inhibitors*
  • Stomach / drug effects
  • Tetrahydroisoquinolines*

Substances

  • Heterocyclic Compounds, 2-Ring
  • Isoquinolines
  • Ligands
  • Receptor, Cholecystokinin B
  • Receptors, Cholecystokinin
  • Tetrahydroisoquinolines
  • 1,2,3,4-tetrahydroisoquinoline carboxylic acid
  • Phenylalanine