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

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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.