Twenty years of non-peptide CCK₁ receptor antagonists: all that glitters is not gold

Abstract

During the last 20 years, pharmaceutical industry and academic efforts have led to several structurally unrelated classes of non-peptide cholecystokinin-1 receptor (CCK₁-R) antagonists. Due to the lack of high resolution structure of CCK₁-R and its peptide ligand, different strategies to design antagonists have been adopted. The rational design, based on conformational studies of the endogenous ligand, has provided the so-called ‘peptoid’ derivatives and conformationally restricted peptoids, whereas all of the other non-peptide antagonists derived by empirical and/or conventional approaches, including the chemical manipulation of natural products, disconnection strategies and the use of single key amino acids. All of these strategies include a final optimisation step of the obtained lead compound performed by chemical modifications. The CCK₁-R antagonists, in addition to providing a better characterisation of the CCK₁-R receptor subtype as pharmacological tools and improving the knowledge of the physiological and pathological role(s) of CCK, may possess therapeutic potential in humans. As the complex biological effects of CCK mediated by CCK₁-R in the CNS are not yet completely established, the therapeutic potential of these antagonists at present is limited to the gastrointestinal system disorders. Up until now, loxiglumide and its R-enantiomer (dexloxiglumide) along with lintitript are the CCK₁-R antagonists at the most advanced stage of clinical research in gastroenterology.

Keywords::

• antagonists
• CCK
• CCK₁
• CCK_A
• cholecystokinin
• drug applications

Acknowledgements

The authors dedicate this review article to their ‘maestro’ of Medicinal Chemistry, Professor Carlo Nisi on occasion of his retirement. The authors wish to not apply the reference annotations for two principal reasons. Firstly, on the basis of their isocratic concept, every single, even small, contribution to the progress of a scientific thematic is worthy of interest. Thus, all the colleagues reported in bibliography are gratefully acknowledged. Secondly, on the basis of their isodynamic concept, should be forced to add three more asterisks on their contribution as they have operated and operate in extremely poor research conditions thanks to the unequal and ungenerous national and local investment (€4000 per year) in the CCK field.