The synthesis and evaluation of small organic molecules as cholecystokinin antagonists

Singh, Harjit (2002). The synthesis and evaluation of small organic molecules as cholecystokinin antagonists. PHD thesis, Aston University.

Abstract

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.

Divisions: Life & Health Sciences
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Institution: Aston University
Uncontrolled Keywords: cholecystokinin,(CCKA/1 & CCKB/2) receptor antagonists,anxiety, 1,4-Benzodiazepine template ,Pyrazolyl/Pyrazolinone ureido-amide derivatives ,Furan-2(5)-one anlogues ,lead structure
Completed Date: 2002-02
Authors: Singh, Harjit

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