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 gamma-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.
Dolbeare
Kristine
K
Department of Medicinal Chemistry, University of Minnesota, 308Harvard St. SE, Minneapolis, MN 55455, USA.
Pontoriero
Giuseppe F
GF
Gupta
Suresh K
SK
Mishra
Ram K
RK
Johnson
Rodney L
RL
D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000378:metabolism; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D007769:Lactams / Q000138:chemical synthesis* / Q000494:pharmacology; D018716:Molecular Mimicry; D011485:Protein Binding; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D011869:Radioligand Assay; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D015259:Dopamine Agents; D007769:Lactams; D011760:Pyrrolidinones; D011954:Receptors, Dopamine; C067487:3-(N-prolylamine)-2-oxo-1-pyrrolidineacetamide; C009074:N-n-propylnorapomorphine; D001058:Apomorphine