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Design, synthesis and evaluation of a PLG tripeptidomimetic based on a pyridine scaffold.
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- Saitton, Stina, 1972 (author)
- Umeå universitet,Gothenburg University,Göteborgs universitet,Institutionen för kemi,Department of Chemistry,Kemiska institutionen
- Del Tredici, Andria L (author)
- Mohell, Nina (author)
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- Vollinga, Roeland C (author)
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- (creator_code:org_t)
- 2004-11-18
- 2004
- English.
- In: Journal of medicinal chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 47:26, s. 6595-602
- Journal article (peer-reviewed)
Abstract
Subject headings
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- A 2,3,4-substituted pyridine derivative has been identified as a potential tripeptidomimetic scaffold. The design of the scaffold was based on conformational and electrostatic comparisons with a natural tripeptide. The scaffold has been used in the synthesis of a Pro-Leu-Gly-NH2 (PLG) mimetic. The different substituents in the 2-, 3-, and 4-positions of the pyridine ring were introduced via an aromatic nucleophilic substitution reaction, a "halogen-dancing" reaction, and a Grignard coupling of a Boc-protected amino aldehyde, respectively. The synthetic route involves eight steps and provides the mimetic in 20% overall yield. The pyridine based PLG-mimetic was evaluated for its ability to enhance the maximum response of the dopamine agonist N-propylapomorphine (NPA) at human D2 receptors using a cell based assay (the R-SAT assay). The dose-response curve of the mimetic was found to exhibit a down-turn phase, similar to that of PLG. In addition, the mimetic was more potent than PLG to enhance the NPA response; the maximum response was found to be 146% at 10 nM concentration, as compared to 115% for PLG at the same concentration. Interestingly, conformational analysis by molecular modeling showed that the pyridine mimetic cannot adopt a type II beta-turn conformation that previously has been suggested to be the bioactive conformation of PLG.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Keyword
- Acetamides
- chemical synthesis
- chemistry
- pharmacology
- Animals
- Apomorphine
- analogs & derivatives
- pharmacology
- Crystallography
- X-Ray
- Dopamine Agents
- chemical synthesis
- chemistry
- pharmacology
- Drug Synergism
- Humans
- Hydrogen Bonding
- MSH Release-Inhibiting Hormone
- chemistry
- Mice
- Models
- Molecular
- Molecular Mimicry
- Molecular Structure
- NIH 3T3 Cells
- Protein Structure
- Secondary
- Pyridines
- chemical synthesis
- chemistry
- pharmacology
- Receptors
- Dopamine D2
- agonists
- Structure-Activity Relationship
Publication and Content Type
- ref (subject category)
- art (subject category)
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