Back to Search
Start Over
Ring Size in Octreotide Amide Modulates Differently Agonist versus Antagonist Binding Affinity and Selectivity
- Publication Year :
- 2008
-
Abstract
- H-DPhe (2)-c[Cys (3)-Phe (7)-DTrp (8)-Lys (9)-Thr (10)-Cys (14)]-Thr (15)-NH2 (1) (a somatostatin agonist, SRIF numbering) and H-Cpa (2)-c[DCys (3)-Tyr (7)-DTrp (8)-Lys (9)-Thr (10)-Cys (14)]-Nal (15)-NH2 (4) (a somatostatin antagonist) are based on the structure of octreotide that binds to three somatostatin receptor subtypes (sst 2/3/5) with significant binding affinity. Analogues of 1 and 4 were synthesized with norcysteine (Ncy), homocysteine (Hcy), or D-homocysteine (DHcy) at positions 3 and/or 14. Introducing Ncy at positions 3 and 14 constrained the backbone flexibility, resulting in loss of binding affinity at all sst s. The introduction of Hcy at positions 3 and 14 improved selectivity for sst 2 as a result of significant loss of binding affinity at the other sst s. Substitution by DHcy at position 3 in the antagonist scaffold (5), on the other hand, resulted in a significant loss of binding affinity at sst 2 and sst 3 as compared to the different affinities of the parent compound (4). The 3D NMR structures of the analogues in dimethylsulfoxide are consistent with the observed binding affinities.
- Subjects :
- Agonist
Models, Molecular
endocrine system
Magnetic Resonance Spectroscopy
medicine.drug_class
Stereochemistry
Stereoisomerism
Octreotide
Article
Cell Line
chemistry.chemical_compound
Radioligand Assay
Structure-Activity Relationship
Drug Discovery
medicine
Peptide synthesis
Structure–activity relationship
Humans
Cysteine
Receptors, Somatostatin
Molecular Structure
Chemistry
Somatostatin receptor
Antagonist
Somatostatin
Molecular Medicine
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....4f017e3ea6615ab9694102e5053a7c64