Synthesis and Dopamine Receptor Modulating Activity of Lactam Conformationally Constrained Analogues of Pro-Leu-Gly-NH2

Uma Sreenivasan, Ram K. Mishra, Rodney L. Johnson

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57 Scopus citations

Abstract

A series of analogues of the potent analogue of Pro-Leu-Gly-NH2 (PLG), 2-oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1-pyrrolidineacetamide (2) were synthesized in which the (R)-γ-lactam residue of 2 was replaced with a (R)-β-lactam, (R)-aminosuccinimide, (R)-cycloseryl, (R)-δ-lactam, (R)-ϵ-lactam, or (S)-ϵ-lactam residue to give analogues 3–8, respectively. These substitutions were made so as to vary the ψ2 torsion angle. The analogues were tested for their ability to enhance the binding of the dopamine receptor agonist ADTN to the dopamine receptor. Analogues 3–6 and 8 exhibited dose-response curves that were bell-shaped in nature with the maximum effect occurring at a concentration of 1 µM. Analogue 7 was inactive. Analogues 3 and 4 were found to be as effective as PLG, while analogues 5, 6, and 8 appeared to be more effective than PLG in terms of enhancing the binding of ADTN to dopamine receptors. The activity of analogues 3–6 and 8 with their ψ2 angles in the vicinity of that observed in a type II β-turn is consistent with the hypothesis that this type of turn is the bioactive conformation of PLG.

Original languageEnglish (US)
Pages (from-to)256-263
Number of pages8
JournalJournal of medicinal chemistry
Volume36
Issue number2
DOIs
StatePublished - 1993

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