Allosteric Modulation of the Dopamine D2 Receptor by Pro-Leu-Gly-NH2 Peptidomimetics Constrained in Either a Polyproline II Helix or a Type II β-Turn Conformation
| Autor: | Kevin Skoblenick, Swapna Bhagwanth, Ram K. Mishra, Rodney L. Johnson, Niran Argintaru, Bhooma Raghavan |
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| Rok vydání: | 2009 |
| Předmět: |
Stereochemistry
Peptidomimetic Allosteric regulation Stereoisomerism In Vitro Techniques Crystallography X-Ray Binding Competitive Heterocyclic Compounds 2-Ring Protein Structure Secondary Article Structure-Activity Relationship Allosteric Regulation Dopamine receptor D2 Drug Discovery Animals Structure–activity relationship Spiro Compounds Protein secondary structure Polyproline helix Receptors Dopamine D2 Chemistry Molecular Mimicry Corpus Striatum MSH Release-Inhibiting Hormone Dopamine receptor Thiazolidines Molecular Medicine Cattle Peptides Oligopeptides |
| Zdroj: | Journal of Medicinal Chemistry. 52:2043-2051 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm801575w |
| Popis: | Type II beta-turn mimics and polyproline II helix mimics based upon diastereoisomeric 5.6.5 spiro bicyclic scaffolds have provided two pairs of Pro-Leu-Gly-NH(2) (PLG) peptidomimetics with contrasting dopamine receptor modulating activities. Compounds 1a and 3a were found to be positive allosteric modulators of the dopamine receptor, while the corresponding diastereoisomeric compounds 1b and 3b provided the first PLG peptidomimetics with the ability to decrease the binding of agonists to the dopamine receptor. The positive allosteric modulating activity of 3a supported the hypothesis that a polyproline II helix conformation is the bioactive conformation for the PLG analogue Pro-Pro-Pro-NH(2). The results also show that a change in the bridgehead chirality of the 5.6.5 scaffold brings about opposite effects in terms of the modulation of the dopamine receptor. |
| Databáze: | OpenAIRE |
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