Design, synthesis, X-ray analysis, and dopamine receptor-modulating activity of mimics of the "C5" hydrogen-bonded conformation in the peptidomimetic 2-oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1- pyrrolidineacetamide.

doi:10.1021/JM00048A003

Paper

Design, synthesis, X-ray analysis, and dopamine receptor-modulating activity of mimics of the "C5" hydrogen-bonded conformation in the peptidomimetic 2-oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1- pyrrolidineacetamide.

Published Oct 1, 1994 · P. Baures, P. Baures, W. Ojala

Journal of medicinal chemistry

Q1 SJR score

20

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0

Influential Citations

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Abstract

3(R)-(7a(S)-Hexahydro-1-oxo-3,3-dimethyl-1H-pyrrolo[1,2-c]imidazol-2-yl) - oxo-1-pyrrolidine-acetamide (2) and 3(R)-[1-(2,5-dioxopyrrolidino[3,4-c]piperazino)]-2-oxo-1- pyrrolidineacetamide (3) were designed and prepared as mimics of the "C5" hydrogen-bonded structure found in the crystal structure of 2-oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1- pyrrolidineacetamide (1). Both compounds effectively restrict the psi 1 torsional angle to very near the value found in the X-ray structure of 1 as seen in the X-ray crystallographic determination of 2 and methyl 3(R)-[1-(2,5-dioxopyrrolidino[3,4-c]piperazino)]-2-oxo-1- pyrrolidineacetate (11), a diketopiperazine intermediate in the synthesis of 3. These analogs were tested for their ability to enhance the binding of the dopamine D2 receptor agonist N-propylnorapomorphine (NPA) in the absence and presence of 5'-guanylylimidodiphosphate (Gpp(NH)p). Both compounds enhanced [3H]-NPA binding in a dose-dependent manner by increasing both the binding affinity of the agonist and the number of high-affinity sites available for binding. Both 2 and 3 also attenuated the Gpp(NH)p-induced conversion of D2 receptor high-affinity states to the low-affinity states.

In Vitro Study

Study Snapshot

Mimics of the "C5" hydrogen-bonded conformation in the peptidomimetic 2-oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1-pyrrolidineacetamide (1) enhance dopamine D2 receptor binding by increasing

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Design, synthesis, X-ray analysis, and dopamine receptor-modulating activity of mimics of the "C5" hydrogen-bonded conformation in the peptidomimetic 2-oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1- pyrrolidineacetamide.

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References

Citations

Discovery of New Potent Positive Allosteric Modulators of Dopamine D2 Receptors: Insights into the Bioisosteric Replacement of Proline to 3-Furoic Acid in the Melanostatin Neuropeptide.

3-Furoic acid can effectively replace l-proline in the Melanostatin neuropeptide, offering a new avenue for developing anti-Parkinson therapeutics targeting dopamine D2 receptors.

Amide Bond Bioisosteres: Strategies, Synthesis and Successes.

Amide bond bioisosteres can enhance drug potency, selectivity, pharmacokinetic properties, eliminate toxicity, and secure intellectual property, offering new avenues in drug design and development.

Synthesis, Pharmacological and Biological Evaluation of MIF-1 Picolinoyl Peptidomimetics as Positive Allosteric Modulators of D2R.

Picolinoyl-based peptidomimetic 6b shows potential as a positive modulator of dopamine D2 receptors with a pharmacological and toxicological profile similar to MIF-1.

Azopeptides: Synthesis and Pericyclic Chemistry.

Azopeptides can be synthesized and used in pericyclic chemistry to construct constrained aza-pipecolyl and reactive aza-allylglycyl residues.

Méthodologie pour la synthèse combinatoire d’azapeptides: application à la synthèse d’analogues aza-GHRP-6 en tant que ligands du récepteur CD36

This study developed a new method for combinatorial synthesis of azapeptides, enabling the synthesis of aza-GHRP-6 analogs with enhanced receptor selectivity and anti-angiogenic properties.