Synthesis of Novel Pyrrolo[3,4‐d]pyrazole‐dicarboxylic Acids and Evaluation of Their Interaction with Glutamate Receptors

Abstract

Chiral pyrazoline amino acids (3aR,4S,6aR)-1a and (3aR,4S,6aR)-1b, and (3aS,6S,6aS)-2a and (3aS,6S,6aS)-2b, which are conformationally constrained analogues of glutamic and homoglutamic acid, respectively, were prepared via a strategy based on the 1,3-dipolar cycloaddition of a nitrile imine to methyl N-Boc-3,4-didehydro-(S)-prolinate. The new 'amino acids' were tested for activity at ionotropic glutamate receptors. Solely the derivative (3aR,4S,6aR)-1a, which is structurally related to the previously described 4,5-dihydroisoxazole analogue (S)-CIP-A, turned out to be a potent and selective agonist for the AMPA receptors. The biological activity is due to the interaction with the orthosteric glutamate binding site.

Novel 3‐Carboxy‐ and 3‐Phosphonopyrazoline Amino Acids as Potent and Selective NMDA Receptor Antagonists: Design, Synthesis, and Pharmacological Characterization

“…Melting points were determined on a model B 540 Büchi apparatus and are uncorrect- . Ethyl-2-chloro-2-(phenylhydrazone)acetate 7 [13] (2.22 g, 9.81 mmol) and solid NaHCO 3 (2.75 g, 32.7 mmol) were added to a solution of methyl 2-tert-butoxycarbonylaminopent-4-enoate (AE )-6 [11] (1.50 g, 6.54 mmol) in EtOAc (25 mL). The mixture was stirred vigorously for 24 h; progress of the reaction was followed by TLC [petroleum ether (PE)/EtOAc, 7:3].…”

“…Materials and methods 1 H NMR and 13 C NMR spectra were recorded with a Varian Mercury 300 (300 MHz) spectrometer. Chemical shifts (d) are expressed in ppm, and coupling constants (J) are expressed in Hz.…”

“…[13] The cycloaddition reaction produced a mixture of stereoisomers (AE )-8 and (AE )-9 in an approximate 1:1 ratio, as estimated by 1 H NMR spectroscopy. Chromatographic separation of the two stereoisomers was unsuccessful at this stage; therefore, the mixture was treated with a 30 % solution of trifluoroacetic acid (TFA) in dichloromethane to remove the N-Boc protecting group.…”

“…[12] Based on these results, we decided to pursue the design of new NMDA receptor antagonists with improved affinity and a higher degree of subtype selectivity. According to our previous experience, [13] replacement of the D…”

Efficient synthesis of kainic acid analogues

“…In such a way we were able to modulate their pharmacological profile on passing from agonists to antagonists or to generate a remarkable selectivity for one of the three iGluRs. [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] In the planned derivatives, we always preserved the aminoacid moiety because the X-ray structural analyses of the iGluRs bilobular ligand-binding core in complex with agonists or antagonists evidenced the crucial role played by such a group. 31 In a recent paper, 32 it was described a series of derivatives generated by the incorporation of the structural elements of both kainic acid and neodysiherbaine A (neoDH), two naturally occurring pro-convulsant agents.…”