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Ring size in octreotide amide modulates differently agonist versus antagonist binding affinity and selectivity.
Christy Rani R Grace1, Judit Erchegyi, Manoj Samant
1Structural Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Journal of Medicinal Chemistry
|April 16, 2008
Summary
Somatostatin receptor (sst) analogues were modified with different amino acids to alter binding affinity. Homocysteine (Hcy) analogues showed improved selectivity for sst 2, while norcysteine (Ncy) analogues lost binding affinity.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Structural Biology
Background:
- Octreotide-based somatostatin analogues target somatostatin receptor subtypes (sst 2/3/5).
- Understanding structure-activity relationships is crucial for developing selective receptor modulators.
Purpose of the Study:
- To synthesize and characterize novel somatostatin analogues with modified cysteine residues at positions 3 and/or 14.
- To evaluate the impact of norcysteine (Ncy), homocysteine (Hcy), and D-homocysteine (DHcy) substitutions on receptor binding affinity and selectivity.
Main Methods:
- Synthesis of somatostatin agonist and antagonist analogues incorporating Ncy, Hcy, or DHcy.
- Binding affinity assays for somatostatin receptor subtypes (sst 2/3/5).
- 3D Nuclear Magnetic Resonance (NMR) structural analysis in dimethylsulfoxide (DMSO).
Main Results:
- Ncy substitution at positions 3 and 14 reduced binding affinity across all sst subtypes due to backbone constraint.
- Hcy substitution at positions 3 and 14 enhanced selectivity for sst 2 by decreasing affinity for other subtypes.
- DHcy substitution at position 3 of the antagonist scaffold significantly reduced binding affinity for sst 2 and sst 3.
Conclusions:
- Amino acid substitutions at positions 3 and 14 significantly modulate somatostatin receptor binding profiles.
- Hcy analogues demonstrate potential for selective sst 2 targeting.
- 3D NMR structures correlate with observed binding affinities, providing insights into molecular interactions.
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