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.
Saitton
Stina
S
Department of Chemistry, Medicinal Chemistry, Göteborg University, SE-412 96 Göteborg, Sweden.
Del Tredici
Andria L
AL
Mohell
Nina
N
Vollinga
Roeland C
RC
Boström
Dan
D
Kihlberg
Jan
J
Luthman
Kristina
K
D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D006860:Hydrogen Bonding; D009075:MSH Release-Inhibiting Hormone / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D017433:Protein Structure, Secondary; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists; D013329:Structure-Activity Relationship
C495229:2-(3-isobutyl-4-(pyrrolidine-2-carbonyl)pyridin-2-yloxy)acetamide; D000081:Acetamides; D015259:Dopamine Agents; D011725:Pyridines; D017448:Receptors, Dopamine D2; C009074:N-n-propylnorapomorphine; D009075:MSH Release-Inhibiting Hormone; D001058:Apomorphine