Rationally Designed "Dipeptoid" Analogues of CCK. Alpha-Methyltryptophan Derivatives as Highly Selective and Orally Active Gastrin and CCK-B Antagonists With Potent Anxiolytic Properties

J Med Chem. 1991 Jan;34(1):404-14. doi: 10.1021/jm00105a062.

Abstract

This paper describes the synthesis and structure-activity relationships (SAR) leading to the first rational design of "dipeptoid" analogues of the neuropeptide cholecystokinin (CCK). Compounds [R-(R*,S*)]-4-[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[(tricyclo [3.3.1.1(3,7)]dec-2-yloxy)carbonyl]amino]propyl]amino]-3- phenylpropyl]-amino]-4-oxo-2-butenoic acid, [R-(R*,R*)]-4-[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[(tricyclo [3.3.1.1(3,7)]dec-2-oxy)carbonyl]amino]propyl]amino]-1- phenylethyl]amino]-4-oxo-2-butenoic acid, and [R-(R*,R*)]-4-[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[(tricyclo [3.3.1.1(3,7)]dec-2-yloxy)carbonyl]amino]propyl]amino]-1- phenylethyl]amino]-4-oxobutanoic acid (29d) have CCK-B binding affinities of IC50 = 0.8, 0.7, and 1.7 nM with a CCK-A/CCK-B ratio of 550, 1100, and 2500, respectively. Compound 27 is well-absorbed and is equiactive by the subcutaneous (sc) and intravenous (iv) routes of administration in the Ghosh and Schild test in rats in inhibiting pentagastrin stimulated gastric acid secretion with ED50 = 0.07 (0.01-0.34) mumol/kg. Compound 29d is anxiolytic in mice in the black-white test box over the range 0.0001-30 mg/kg sc, comparable in activity to diazepam over the range 0.125-1 mg/kg ip), and also active in this test when dosed orally over a wide range from 0.0001 to 10 mg/kg.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Anti-Anxiety Agents / chemical synthesis*
  • Cerebral Cortex / metabolism
  • Cholecystokinin / analogs & derivatives*
  • Cholecystokinin / antagonists & inhibitors
  • Cholecystokinin / chemical synthesis*
  • Cholecystokinin / pharmacology
  • Gastrins / antagonists & inhibitors*
  • Indicators and Reagents
  • Male
  • Mice
  • Receptors, Cholecystokinin / drug effects*
  • Receptors, Cholecystokinin / metabolism
  • Structure-Activity Relationship

Substances

  • Anti-Anxiety Agents
  • Gastrins
  • Indicators and Reagents
  • Receptors, Cholecystokinin
  • Cholecystokinin