Development of peptidomimetic ligands of Pro-Leu-Gly-NH₂ as allosteric modulators of the dopamine D₂ receptor

• Swapna Bhagwanth,
• Ram K. Mishra and
• Rodney L. Johnson

Beilstein J. Org. Chem. 2013, 9, 204–214, doi:10.3762/bjoc.9.24

• changes in the spiro-bicyclic dopamine receptor modulators are capable of causing major changes in the modulatory activity of PLG peptidomimetics. Keywords: allosteric modulation; dopamine D2 receptor; peptidomimetic; Pro-Leu-Gly-NH2; spiro-bicyclic scaffold; Review There has been an increasing effort

• that define a turn structure, Φ2, ψ2, and Φ3, making them among the best scaffolds at locking a peptide into a turn structure. The 5.5.5 spiro-bicyclic scaffold of peptidomimetic 27 (Figure 5) was found to mimic a type II β-turn as demonstrated through computational studies [44]. Peptidomimetic 27 was

• chirality at the C-8’a bridgehead carbon atom. This difference, it was postulated, has an effect on the conformation adopted by the thiazolidine ring within the spiro-bicyclic scaffold. In particular, modelling studies suggested that the pucker of the thiazolidine ring in negative modulators 29b and 49b