Design, synthesis and evaluation of a PLG tripeptidomimetic based on a pyridine scaffold.

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medicinal Chemistry (hsv//eng)

Nyckelord

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

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