beta-Turned dipeptoids as potent and selective CCK(1) receptor antagonists

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Molecular Biology

Background:

• Previous work established that replacing alpha-MeTrp residues in dipeptoids with the IBTM skeleton yields potent CCK(1) receptor antagonists.
• Understanding the bioactive conformation of CCK(1) antagonists is crucial for developing selective therapeutics.
• The role of the C-terminal residue and beta-turn type in receptor interaction requires further elucidation.

Purpose of the Study:

• To synthesize and characterize novel dipeptoid analogues based on the IBTM framework.
• To investigate the impact of C-terminal modifications and beta-turn mimetics on CCK(1) receptor binding affinity and selectivity.
• To explore the structure-activity relationships governing CCK(1) receptor antagonism.

Main Methods:

• Synthesis of new dipeptoid analogues incorporating different IBTM frameworks and C-terminal residues.
• Evaluation of binding affinity and selectivity for CCK(1) receptors using radioligand binding assays.
• Assessment of functional activity as CCK(1) receptor antagonists.

Main Results:

• A C-terminal free carboxylic acid and an S configuration of Phe and betaHph residues favor CCK(1) receptor recognition.
• The type of beta-turn mimetic critically influences CCK(1) receptor subtype selectivity.
• Compound 15a, featuring a type II' IBTM mimetic, exhibited approximately 6-fold higher CCK(1) selectivity compared to analogue 16a (type II mimetic), with both showing nanomolar affinity.
• Both compounds 15a and 16a demonstrated CCK(1) receptor antagonist activity.

Conclusions:

• The beta-turn-like conformation within the dipeptoid backbone is proposed to contribute to the bioactive conformation at the CCK(1) receptor.
• Structural modifications, particularly the beta-turn type, significantly impact CCK(1) receptor antagonist selectivity.
• These findings provide valuable insights for the design of more selective CCK(1) receptor antagonists.