iso-Lactam and reduced amide analogues of the peptidomimetic dopamine receptor modulator 3( R)-[(2( S)-Pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide

An analogue of the highly potent γ-lactam Pro-Leu-Gly-NH 2 peptidomimetic, 3( R)-[(2( S)-pyrrolidinylcarbonyl) amino]-2-oxo-1-pyrrolidineacetamide ( 2), 4( R)-[[2( S)-pyrrolidinylcarbonyl]amino]-2-oxo-1-pyrrolidineacetamide ( 3), in which the lactam carbonyl moiety has been placed in a different pos...

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Published in:Bioorganic & medicinal chemistry 2003-09, Vol.11 (18), p.4103-4112
Main Authors: Dolbeare, Kristine, Pontoriero, Giuseppe F, Gupta, Suresh K, Mishra, Ram K, Johnson, Rodney L
Format: Article
Language:English
Subjects:
Animals
Apomorphine - analogs & derivatives
Apomorphine - metabolism
Biological and medical sciences
Catecholaminergic system
Cattle
Cell Membrane - drug effects
Cell Membrane - metabolism
Corpus Striatum - drug effects
Corpus Striatum - metabolism
Dopamine Agents - chemical synthesis
Dopamine Agents - pharmacology
In Vitro Techniques
Lactams - chemical synthesis
Lactams - pharmacology
Medical sciences
Molecular Mimicry
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Protein Binding
Pyrrolidinones - chemical synthesis
Pyrrolidinones - pharmacology
Radioligand Assay
Receptors, Dopamine - drug effects
Receptors, Dopamine - metabolism
Structure-Activity Relationship
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Summary:An analogue of the highly potent γ-lactam Pro-Leu-Gly-NH 2 peptidomimetic, 3( R)-[(2( S)-pyrrolidinylcarbonyl) amino]-2-oxo-1-pyrrolidineacetamide ( 2), 4( R)-[[2( S)-pyrrolidinylcarbonyl]amino]-2-oxo-1-pyrrolidineacetamide ( 3), in which the lactam carbonyl moiety has been placed in a different position with respect to the 3-amino group was synthesized. Also, a series of analogues of 2, compounds 4– 6, were synthesized in which each of the amide bonds of 2 were systematically replaced with a reduced amide bond surrogate. The analogues were tested for their ability to enhance the binding of [ 3H] N-propylnorapomorphine to dopamine receptors in a functional in vitro assay utilizing bovine striatal membranes. Peptidomimetic 3 was shown to be more potent than 2, while 4 and 5 were significantly less effective than 2. Peptidomimetic 6 had a pharmacological profile similar to that of 2. Graphic
ISSN:0968-0896
1464-3391
DOI:10.1016/S0968-0896(03)00396-1