Synthesis and biological evaluation of analogs of Pro-Leu-Gly-NH2 modified at the leucyl residue

Abstract

A series of analogues of Pro-Leu-Gly-NH2 (PLG) in which the leucine residue has been replaced with the aliphatic amino acids L-isoleucine, L-2-aminohexanoic acid (Ahx), L-2-aminopentanoic acid, and L-2-aminobutanoic acid and the aromatic amino acids L-phenylalanine, L-phenylglycine, L- and D-2-amino-4-phenylbutanoic acid, L-O-methyltyrosine, and L-4-nitrophenylalanine have been synthesized. These analogues were tested for their ability to enhance the binding of the dopamine receptor agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) to striatal dopamine receptors. Two of the above analogues, Pro-Ahx-Gly-NH2 (3) and Pro-Phe-Gly-NH2 (6), showed significant activity in this assay system. Pro-Ahx-Gly-NH2 produced a 16% enhancement of ADTN binding at 0.1 microM, while Pro-Phe-Gly-NH2 enhanced the binding of ADTN by 31% at a concentration of 1 microM.

Allosteric Modulation of the Dopamine Receptor by Conformationally Constrained Type VI β-Turn Peptidomimetics of Pro-Leu-Gly-NH2

“…Previous work has shown that PLG analogues and peptidomimetics with a hydrophobic moiety placed in this topological region possess enhanced dopamine receptor modulating activity. [26][27][28] The activity of 7 and 8 supports the hypothesis that the homochiral prolyl peptides 3 and 5 may assume a type VI β-turn as their bioactive conformation and that such a conformation is able to initiate a modulatory response because it can present the necessary topological arrangement of important pharmacophore moieties in a manner similar to that of PLG peptidomimetics that assume a type II β-turn bioactive conformation. In this regard, the data indicate that the amide NH 2 group may be a more important pharmacophore group than the carboxamide carbonyl group in activating the D 2 receptor allosteric modulatory site, as the major difference between a type II β-turn conformation and a type VI β-turn conformation is the nearly 109° difference in orientation of the carboxamide carbonyl groups.…”

Synthesis and Dopamine Receptor Modulating Activity of Substituted Bicyclic Thiazolidine Lactam Peptidomimetics of l-Prolyl-l-leucyl-glycinamide

“…14 Previous work had shown this side chain to be important for the activity of Pro-Leu-Gly-NH 2 as replacing the side chain with lower alkyl moieties resulted in analogues that posessed little or no activity. 18 In contrast, replacing the isobutyl side chain with the butyl or benzyl group yielded analogues that retained the ability to modualte dopamine receptors.…”

“…Although this analogue lacked the side chain that corresponds to the isobutyl group of the leucine residue found in 1 , it proved to be one of the most effective analogues tested thus far. Nevertheless, since earlier SAR studies with linear tripeptide analogues of 1 modified at the leucine position showed that a hydrophobic residue at this position was important for activity, we postulated that incorporation of the hydrophilic side chain into the structure of 2 would enhance further the activity of this peptidomimetic. To test this hypothesis, the synthesis of the 6-substituted bicyclic thiazolidine lactams 3 − 5 was undertaken.…”

Synthesis and dopamine receptor modulating activity of lactam conformationally constrained analogs of Pro-Leu-Gly-NH2

“…The aqueous phase was washed once with EtOAc (50 mL) and the organic phases were combined, dried over MgS04, filtered, and concentrated in vacuo to an oil. MPLC (EtOAc/hexanes, 3:2) of the oil afforded 5.44 g (91.8%) of 16a as a clear oil: [ ] 0 = -22.8°(c 0.143, CHC13); NMR (200 MHz, CDCL) 5.91 (br d, 1 H, J = 6.6 Hz, OCONH), 4.42 (dd, 1 H, J = 6.1 and 10.5 Hz, 3-CH), 4.16 (s, 2 H, CH2C02), 3.72 (s, 1H, OCH3), 3.61-3.76 (m, 1H, 7-CH2), 3.16 (dd, 1H ,J-4.8 and (OCON), 79.4 (Me3C), 53.5 (3-C), 52.2 (OCH3), 50.7 (CH2C02 and 7-CH2), 32.6 (4-C), 28.5 ((CH3)3C), 27.1 and 28.0 (5,6-C);…”