Dopamine receptor modulation by conformationally constrained analogs of Pro-Leu-Gly-NH2

Abstract

Two series of conformationally constrained analogues of Pro-Leu-Gly-NH2 (PLG) have been synthesized. In one series of analogues, the Leu-Gly-NH2 dipeptide segment of PLG was replaced with the gamma-lactam residues 3(S)- and 3(R)-amino-2-oxopyrrolidineacetamide and the delta-lactam residue 3(S)-amino-2-oxopiperidineacetamide. The corresponding gamma-lactam analogues of less than Glu-Leu-Gly-NH2 were also synthesized. In a second series of analogues, the glycinamide residue of PLG was replaced with the 2-ketopiperazine, 3(S)-amino-2-pyrrolidone, and 3(S)-amino-2-piperidone residues. The above 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. Of the conformationally constrained analogues of PLG synthesized in this study, only the gamma-lactam analogue 3(R)-(N-L-prolylamino)-2-oxo-1-pyrrolidineacetamide (3) was found to possess significant activity. This analogue was 10,000 times more active than PLG, under preincubation conditions. It significantly enhanced the binding of ADTN at concentrations of 10(-9) and 10(-10) M.

Modulation of Agonist Binding to Human Dopamine Receptor Subtypes by l-Prolyl-l-leucyl-glycinamide and a Peptidomimetic Analog

“…CHO cells expressing human DA D 3 receptors were also obtained from Sigma-Aldrich. PAOPA was synthesized as described previously (Yu et al, 1988). Suramin was obtained from Tocris-Cookson Inc. (Ellisville, MO), whereas ascorbic acid was purchased from BDH Inc. (Toronto, ON, Canada).…”

The conformational preferences of ?-lactam and its role in constraining peptide structure

“…It exists in a type II Leu-Gly fl-turn conformation as evidenced by the crystal structure [11,22] data. Pharmacological experiments show that the analogue Pro-D-7-Lac-Gly-NH 2 is 10 000 times more active than the native peptide, in enhancing the binding of a dopamine agonist [7] while the L-yLac analogue is inactive. This led to the structural implication that the D-7-Lac analogue would have a conformation similar to that of the parent peptide and would constrain the peptide into a type II fl-turn.…”

“…7-Lactams have recently found increasing use in the design of peptides to impose constraints on the backbone [3][4][5][6][7]. Analogues of many important bio-active peptides like luteinising hormone releasing hormone (LHRH) [3], and Pro-Leu-Gly-NH2 (which displays a range of pharmacological functions [8] in the central nervous system) incorporate 7-1actams [7].…”

“…Analogues of many important bio-active peptides like luteinising hormone releasing hormone (LHRH) [3], and Pro-Leu-Gly-NH2 (which displays a range of pharmacological functions [8] in the central nervous system) incorporate 7-1actams [7]. The presence of the lactam ring was thought to restrict conformational freedom and force the peptide to adopt a fl-turn [3].…”

Change in expression of vesicular protein synapsin II by chronic treatment with D2 allosteric modulator PAOPA

“…Allosteric modulators are proving to be a promising avenue for the development of more specific, effective and safer drugs [12,13,29]. The current study utilizes the potent allosteric MIF-1 peptidomimetic (3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide, PAOPA) [50], which has shown to effectively prevent and reverse a range of schizophrenia-like behavioral abnormalities [2,15]. Characterization of the pharmacokinetic and toxicological properties of PAOPA have revealed this ligand to have metabolic properties comparable to current marketed antipsychotic drugs, without the movement, hematological and metabolic adverse events commonly associated with the use of these drugs [46].…”