The synthesis and evaluation of small organic molecules as cholecystokinin antagonists

  • Harjit Singh

Student thesis: Doctoral ThesisDoctor of Philosophy


Cholecystokinin (CCK) is a peptide hormone, present in the alimentary and the CNS. It is the most abundant peptide in the brain. CCK has been implicated in a
number of disorders. The link between CCK and anxiety was the basis for this
research. A comprehensive discussion on the many types of CCK receptor antagonists is included. For the drug discovery process, a number of synthetic approaches have been investigated and alternative chemical approaches developed.
1,4-Benzodiazepine analogues were prepared, with substitutents In the 1,2 & 3-
position of the benzodiazepine scaffold varied, and substituted 3-anilino
benzodiazepines exhibited the greatest in vitro activity towards the CCKA receptor subtype. Through extensive screening, pyrazolinone-ureido derivatives were identified, optimised, SAR studied and re-screened. A comprehensive in vivo study on the most active analogue is included, which has a number of common structural features with L-36S, 260 including activity. Pyrazolinone-amide derivatives, bearing the tryptophan moiety were equally active. A number of existing and novel furan- 2(SH)-one building blocks were prepared, from which a selected mini-library of 4- amino-substituted furan-2(SH)-ones were prepared and evaluated. All synthesised compounds were evaluated in a CCK radiolabelled binding assay (CCKA & CCKB), with compounds demonstrating receptor selectivity and lead structures being discovered. The work in this thesis has identified a number of highly active prime structures, from which further investigations are essential in providing more in vitro & in vivo data and the need to prepare more analogues.

Date of AwardFeb 2002
Original languageEnglish
SupervisorEric Lattmann (Supervisor)


  • cholecystokinin
  • (CCKA/1 & CCKB/2) receptor antagonists
  • anxiety
  • 1,4-Benzodiazepine template
  • Pyrazolyl/Pyrazolinone ureido-amide derivatives
  • Furan-2(5)-one anlogues
  • lead structure

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