Synthesis and activity of a potent N-methyl-D-aspartic acid agonist, trans-1-aminocyclobutane-1,3-dicarboxylic acid, and related phosphonic and carboxylic acids

Abstract

We report the synthesis of a series of 3-carboxy-, 3-(carboxymethyl)-, 3-(omega-phosphonoalkyl)-1-aminocyclobutane-1-carboxylic acids for evaluation as agonists or antagonists of neurotransmission at excitatory amino acid receptors, particularly N-methyl-D-aspartic acid (NMDA) receptors. The compounds were evaluated as agonists on their ability to depolarize the rat brain cortical wedge preparation or as antagonist of the actions of the selective agonists NMDA, quisqualic acid, and kainic acid. The chain-elongated glutamate derivatives with potential antagonist activity proved to be weak and frequently nonselective antagonists in this assay. The most noteworthy result was that trans isomer 7b was a very potent agonist, approximately 20 times more active than NMDA at NMDA receptors, while the cis isomer was 1/3 as potent as NMDA.

Rigid nonproteinogenic cyclic amino acids as ligands for glutamate receptors: trans‐Tris(homoglutamic) acids

“…The combined organic extracts were washed with water, brine, dried with MgSO 4 , filtered, concentrated, and finally dried in high vacuum. 13 and (ent-5a), respectively…”

Molecular Pharmacology of the Na+-Dependent Transport of Acidic Amino Acids in the Mammalian Central Nervous System.

“…As pointed out earlier, there has been a wealth of information on the substrate specificity and structural requirements of GluT 19,26,34,[92][93][94][95][96][97][98][99][100][101]103,105,[107][108][109] even in relation to individual EAAT's 110,112,114,[179][180][181][182][183] yet this structure-activity data has not so far been satisfactorily matched with the protein architecture of the putative substrate-binding regions. Moreover, some of the EAAT's may form multimeric complexes 184) and most of them also act as chloride channels 185) ; for a review see ref.…”

“…It was found to have a very high affinity and specificity for GluT 105) (for a review see 13) ) and recent studies using NMR analyses have shown that L-CCG III can be very rapidly accumulated by brain slices, even against steep concentration gradients. 106) Other conformationally-restricted glutamate analogues have been synthesised and used as substrates/inhibitors of GluT [107][108][109] ; for a review see. 110) In some cases, such compounds have been shown to be transporter selective.…”

Mechanism of Action of Low Dose Preparations from <i>Coffea arabica</i>, <i>Gelsemium</i> and <i>Veratrum</i> Based on <i>in Vivo</i> and <i>in Vitro</i> Neurophysiological Findings

“…For stimulation of glutamate receptors (NMDA, AMPA, Kainate and metabotropic receptor) four agonists were used, respectively: trans-1-Aminocyclobutan-1,3-dicarboxylic acid (ACBD [13], (S)-(-)-α-Amino-5-fluoro-3,4-dihydro-2,4-dioxo-1(2H)-pyrimmidinepropanoic acid (S-Fluorowillardiine [14]- [16], (RS)-2-Amino-3-(3-hydroxy-5-tert-butyliosxazol-4-yl)propanoic acid (ATPA; [17]- [20] and (±)-1-Aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD; [21]- [23]. All agonists were tested in pilot experiments in order to detect a concentration leading to strong increases of population spike amplitude in the presence of single stimuli (SS) and theta burst stimulation (TBS).…”