Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Allosteric Regulation
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Animals
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Binding, Competitive
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Cattle
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Corpus Striatum / metabolism
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Crystallography, X-Ray
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Heterocyclic Compounds, 2-Ring / chemical synthesis*
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Heterocyclic Compounds, 2-Ring / chemistry
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Heterocyclic Compounds, 2-Ring / pharmacology
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In Vitro Techniques
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MSH Release-Inhibiting Hormone / chemistry*
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Molecular Mimicry
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Oligopeptides / chemistry
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Peptides / chemistry*
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Protein Structure, Secondary
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Receptors, Dopamine D2 / agonists
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Receptors, Dopamine D2 / metabolism*
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Spiro Compounds / chemical synthesis*
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Spiro Compounds / chemistry
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Spiro Compounds / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Thiazolidines / chemical synthesis*
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Thiazolidines / chemistry
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Thiazolidines / pharmacology
Substances
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1-(2-pyrrolidinylcarbonyl)-5'-oxospiro(pyrrolidine-2,6'-thiazolidino(3,2-a)piperidine)-3'-carboxamide
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Heterocyclic Compounds, 2-Ring
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Oligopeptides
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Peptides
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Pro-Pro-Pro-NH2
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Receptors, Dopamine D2
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Spiro Compounds
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Thiazolidines
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polyproline
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MSH Release-Inhibiting Hormone