Development of somatostatin receptor subtype selective agonists through combinatorial chemistry

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Endocrinology

Background:

• Somatostatin receptors play crucial roles in regulating various physiological processes.
• Developing selective non-peptide agonists is essential for understanding receptor functions and therapeutic applications.

Purpose of the Study:

• To identify novel non-peptide agonists for all five somatostatin receptors (SSTR1-5).
• To utilize combinatorial mixture screening for efficient discovery of subtype-selective ligands.
• To investigate the physiological roles of SSTR2 and SSTR5 in hormone regulation.

Main Methods:

• Screening of combinatorial mixture libraries based on a lead structure identified via molecular modeling.
• Design and synthesis of follow-up libraries, including aryl-indole compounds.
• Iterative deconvolution of active mixtures to identify pure compounds.
• In vitro assays to determine receptor subtype selectivity and functional effects.

Main Results:

• Identification of non-peptide agonists for all five somatostatin receptors with high affinity and subtype selectivity.
• Validation of the combinatorial mixture screening approach for efficient ligand discovery.
• Demonstration of SSTR2's role in inhibiting glucagon release.
• Demonstration of SSTR5's role in mediating insulin secretion.
• Confirmation that both SSTR2 and SSTR5 regulate growth hormone release.

Conclusions:

• Combinatorial mixture screening is an effective and efficient method for discovering subtype-selective receptor agonists.
• The identified agonists provide valuable tools for elucidating the physiological functions of somatostatin receptors.
• SSTR2 and SSTR5 play distinct roles in regulating pancreatic hormone secretion and growth hormone release.