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

Abstract

6-Substituted bicyclic thiazolidine lactam peptidomimetics of Pro-Leu-Gly-NH(2) (1) were synthesized to test the hypothesis that incorporation of a hydrophobic side chain into the bicyclic thiazolidine lactam scaffold would further enhance the dopamine receptor modulating activity of such peptidomimetics. The substituents employed were the isobutyl, butyl, and benzyl groups to give peptidomimetics 3-5, respectively. These peptidomimetics were evaluated in vivo as modulators of apomorphine-induced rotational behavior in the 6-hydroxydopamine-lesioned rat model of hemiparkinsonism and were compared with the unsubstituted bicyclic thiazolidine lactam Pro-Leu-Gly-NH(2) peptidomimetic 2. Peptidomimetics 3-5 each affected rotational behavior in a bell-shaped dose-response relationship producing maximal increases of 44% (1 microgram/kg,ip), 56% (0.1 microgram/kg,ip), and 30% (1 microgram/kg, ip), respectively. In comparison, unsubstituted peptidomimetic 2 increased rotational behavior by only 23% at a dose of 0.1 microgram/kg, ip.

Ring closing metathesis of α- and β-amino acid derived dienes

“…It is interesting to note that this change in protecting group gives rise to compounds with the opposite absolute configuration in the allylation step, but this was not considered of significance. Preparation of the tertiary amide 13 required hydrolysis of the oxazolininone 11 [34] followed by coupling with N-allyl-glycine ethyl ester in the presence of the peptide coupling agent, (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumm hexafluorophosphate (PyAOP). This gave a modest 18% yield of 13.…”

“…Carboxylic acid 12 [34] (302 mg, 0.89 mmol), N-allylglycine ethyl ester (191 mg, 1.34 mmol) and PyAOP (600 mg, 1.16 mmol) were dissolved in anhydrous DMF (20 mL). DIPEA (360 lL, 2.05 mmol) was added and the reaction mixture stirred at rt for 18 h. This was partitioned between EtOAc and 1 M HCl (aq) .…”

Development of peptidomimetic ligands of Pro-Leu-Gly-NH2 as allosteric modulators of the dopamine D2 receptor

“…As in the lactam series, the biological activity of the bicylic derivatives was enhanced by incorporating hydrophobic moieties of the bicyclic ring system that would be in a position to access the hydrophobic pocket believed to be interacting with the leucyl side chain of PLG, peptidomimetics 24 – 26 (Fig. 4) [43]. …”

The Application of Freidinger Lactams and their Analogs in the Design of Conformationally Constrained Peptidomimetics

“…Besides Freidinger lactams, other elements of constraint, e.g. bicyclic lactams, were utilized to give modulators of dopamine receptors [105].…”