Synthesis, receptor binding and activity of iso and azakainoids

Abstract

Two syntheses for the production of an unsubstituted azakainoid are described. The 1,3-dipolar cycloaddition of diazomethane with trans-dibenzyl glutaconate yields a 1-pyrazoline, which may be reduced directly to the pyrazolidine. An unexpected trans-cis isomerization is observed during Hg/Al reduction of the 1-pyrazoline N=N bond. Alternatively, when TMS diazomethane is used as the dipole, the resulting 2-pyrazoline obtained after desilylation may be reduced with NaCNBH3 to provide the trans azakainate analog exclusively. The synthesis of an unsubstituted isokainoid via Michael addition is also described. Glutamate receptor binding assays revealed that the azakaniod has a moderate affinity for unspecified glutamate receptors. Membrane depolarization of Aplysia neurons upon application of the azakainoid demonstrates that it is an ionotropic glutamate receptor agonist.

Kainic Acid-Based Agonists of Glutamate Receptors: SAR Analysis and Guidelines for Analog Design

“…23 It hinted that a closely nested interaction exists between KA's pyrrolidine nitrogen and the protein's binding site. Alternatively, analogs 10 and 11 lacking the C4 isopropene substituent lost most of their activity, 24 suggesting that there is more to KA then simply being a rigid form of glutamic acid.…”

Altered expression of ionotropic L-Glutamate receptors in aged sensory neurons of Aplysia californica

“…The role of kainate iGluR is less clear than NMDAR and AMPAR, and they are the most evolutionarily recent iGluR subtype. Kainate analogs elicited depolarizations and non-desensitizing inward currents in glutamatergic BSC neurons of Aplysia , similar to L-Glu-induced effects in these neurons [23]. Kainate is also an effective agonist in abdominal ganglion neurons [22].…”

Organocatalytic [4+1]-annulation approach for the synthesis of densely functionalized pyrazolidine carboxylates

“…In particular, recent SAR studies have established that aza-kainic acid derivatives (1) have been proven to exhibit potent neuroexcitatory activity. 11 One of the most efficient strategies for the construction of such fused skeletons generally relies on [3+2] cycloadditions of hydrazones to olens in the presence of Bronsted 12 /Lewis 13 acids or with strong heating. 14 Their asymmetric synthesis are also reported employing chiral Zr/BINOL, 15 Si-based Lewis acids, 16 transition metal (Pd, Ni, Au)-catalyzed intramolecular annulations 17 including sequential organocatalysis.…”

“…Aldehydes bearing Br, CN, NO 2 , OMe, SMe and methylenedioxy groups on the aromatic nucleus, and benzyl ether substitutions in aliphatic compounds were found to be well-tolerated under the reaction condition. For all the cases studied, the products 4a-k were indeed obtained in high yields (65-80%) and excellent enantioselectivities (80-94%) with dr > 20 : 1 (Table 1, entry [6][7][8][9][10][11][12][13][14][15][16].…”