Structure-activity relationships of dynorphin a analogues modified in the address sequence.
Article Details
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Schlechtingen G, DeHaven RN, Daubert JD, Cassel JA, Chung NN, Schiller PW, Taulane JP, Goodman M
Structure-activity relationships of dynorphin a analogues modified in the address sequence.
J Med Chem. 2003 May 22;46(11):2104-9.
- PubMed ID
- 12747782 [ View in PubMed]
- Abstract
The peptide [Pro3]Dyn A(1-11)-NH2 2 exhibits high affinity (K(i) = 2.4 nM) and over 2000-fold selectivity for the opioid receptor. Stepwise removal of the C-terminal residues from this ligand demonstrated that its positively charged Arg residues, particularly Arg6 and Arg7, were crucial for binding to the kappa receptor. Analogues shorter than seven amino acids lacked significant affinity for opioid receptors. Comparison with a series of truncated analogues of Dyn A showed that the relative losses in binding potency differed only slightly between the two series. The neutral residues Ile8 and Pro10 could be removed without significant loss in affinity for the kappa receptor. Their replacement, in the Pro3 analogue, with additional Arg residues led to analogues with improved kappa affinity (e.g., [Pro3,Arg8]Dyn A(1-11)-NH2 20: K(i)(kappa) = 0.44 nM). This type of modification did not compromise the high kappa selectivity of the Pro3 analogues. These findings support the view that a negatively charged domain in the putative second extracellular loop of the kappa receptor selectively recognizes residues 6-11 of dynorphin through electrostatic interactions. As with parent compound 2, analogue 20 and related compounds displayed kappa antagonist properties.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Naloxone Kappa-type opioid receptor Ki (nM) 10.7 N/A N/A Details Naloxone Kappa-type opioid receptor EC 50 (nM) 6.6 N/A N/A Details Naloxone Kappa-type opioid receptor IC 50 (nM) 49.8 N/A N/A Details Naloxone Mu-type opioid receptor Ki (nM) 3.63 N/A N/A Details