Design, Synthesis, and Dopamine Receptor Modulating Activity of Diketopiperazine Peptidomimetics ofl-Prolyl-l-leucylglycinamide

Abstract

The diketopiperazine "C5" conformational mimic has been incorporated into the L-prolyl-L-leucylglycinamide (PLG, 1) structure and into the bicyclic lactam PLG peptidomimetic structure 3 to give compounds 5 and 6, respectively. These analogues were designed to explore the idea that the N-terminal "C5" conformation, which was found in the crystal structure of 2 and which was mimicked in 4 by the diketopiperazine function, was a factor in the high potency of these two agents. Through the use of the [3H]spiroperidol/N-propylnorapomorphine (NPA) D2 receptor competitive binding assay, both 5 and 6 were found to increase the affinity of the dopamine receptor for agonists and both were found to increase the percentage of D2 receptors which existed in the high-affinity state. These effects were observed when Gpp(NH)p was either absent or present, and they were analogous to the effects observed previously for PLG and the PLG peptidomimetics 2 and 4. However, the potency seen with 5 and 6 was less than that seen for 2 and 4, suggesting that while the N-terminal "C5" conformation may play a role in the potency of the gamma-lactam peptidomimetics of PLG, it does not appear to be the primary factor. In the 6-hydroxydopamine-lesioned animal model of Parkinson's disease, 5 altered apomorphine-induced rotational behavior in a dose-dependent manner. The maximum effect occurred at a dose of 0.01 mg/kg i.p. and resulted in a 52.27 +/- 13.96% (p < 0.001, n = 7) increase in rotations compared to apomorphine administered alone.

Allosteric modulation of G-protein-coupled receptors

“…Compound 19 caused a maximal increase in rotations of 30% at 1 mg/kg ip., whereas compound 21 and compound 20 at 0.01 mg/kg ip. caused maximal increases of 52% and 191%, respectively [35]. The diproline and triproline analogues of compound 19, Pro-Leu-ProNH 2 , Pro-Leu-(D)ProNH 2 and Pro-Pro-ProNH 2 also enhanced the activity of apomorphine in the rotation test by ~ 30% at 0.1 µg/kg ip., ~ 26% at 1 µg/kg ip.…”

“…All compounds increased the affinity of the agonist significantly, although at different concentrations, PLG at 1000 nM, compound 21 at 100 nM and compounds 20 and 22 at 1 nM. The shift from the high affinity state of the D2 receptor to the low affinity state induced by Gpp(NH)p was attenuated by the compounds resulting in a higher R H / R L ratio (R H = percentage high affinity state, R L = percentage low affinity state) [35].…”

Design, synthesis, and application of azabicyclo[X.Y.0]alkanone amino acids as constrained dipeptide surrogates and peptide mimics

“…Since these earlier efforts, the application of azabicycloalkanone amino acids has intensified in the study of biologically active peptides. Many new enzyme inhibitors and receptor agonists and antagonists have since been reported 85–133…”

“…The specific dihedral angles ψ and ϕ for the active conformation may reflect those measured in the X‐ray structures of analogs 396 and 397 (Figure 22, Table IV). 78, 122, 123…”

Ο ρόλος του ψυχολογικού stress στην έκφραση των πρωτεϊνών hnRNP και DARPP-32 στο Κ.Ν.Σ.

“…Συγκεκριμένα, βρέθηκε ότι η χορήγηση του τριπεπτιδίου Pro-Leu-Gly-NH 2 (PLG ή αλλιώς MIF-1, melanocyte-stimulating hormone release inhibitor factor -1) παρουσιάζει ανασταλτική δράση στην έκφραση της hnRNP-L, γεγονός που υποδεικνύει ότι η ενδοκρανιακή χορήγηση PLG μπορεί να μεταβάλλει την έκφραση γονιδίων, τα οποία συνδέονται με τις hnRNP-L πρωτεΐνες. Επίσης έχει δειχθεί ότι το PLG ασκεί ρυθμιστικό ρόλο στην έκφραση (Rajakumar et al 1986) και τις ικανότητες πρόσδεσης πρωτεϊνών (Baures et al 1997, Baures et al 1994, Mishra et al 1990, Srivastava et al 1988) που εμπλέκονται στην έκφραση δεικτών της ντοπαμινεργικής νευροδιαβίβασης (π.χ. Κατά την ενηλικίωση των επιμύων που υποβλήθηκαν σε στρες μητρικής αποστέρησης αλλά και σε μάρτυρες, μελετήθηκαν οι ακόλουθες παράμετροι:…”