Jan J. Hansen

Glutamic acid agonists. Stereochemical and conformational studies of DL-α-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid (AMPA) and related compounds☆

Microelectrophoretic techniques were used to study the effects of the optical isomers of the L-glutamic acid (GLUT) agonist AMPA on cat spinal neurones. Both enantiomers excited spinal interneurones, L-AMPA being more potent than D-AMPA, and, like GLUT, this excitation was blocked by L-glutamic acid diethyl ester but not by 2-amino-5-phosphonovaleric acid. ATPA and ABPA, in which the methyl group of AMPA was replaced by more bulky substituents, were also GLUT agonists, although weaker than AMPA. O-methyl-AMPA was inactive, suggesting that a necessary condition for GLUT agonist or antagonist actions of this class of compound is the presence of an acidic group in the position equivalent with the omega-position of GLUT.

Naturally-occurring excitatory amino acids as neurotoxins and leads in drug design

The central excitatory neurotransmitter (S)-glutamic acid (Glu) activates at least three types of receptors the NMDA, AMPA, and kainic acid (KAIN) receptors. These receptors mediate the neurotoxicity of a number of naturally-occurring Glu analogues. Thus, domoic acid, a KAIN receptor agonist, has probably been the cause of severe neurologic illness in people who consumed domoic acid poisoned food. beta-N-oxalylaminoalanine (beta-ODAP), an AMPA receptor agonist, has been associated with lathyrism, a spastic paraparesis caused by dietary intake of Lathyrus sativus. The neurotoxic Amanita muscaria constituent ibotenic acid, a nonselective NMDA receptor agonist, has been used as a lead structure for the development of the specific NMDA receptor agonist AMAA, AMPA, and a number of therapeutically interesting AMPA and KAIN receptor agonists.

Hydroxylated analogues of 5-aminovaleric acid as 4-aminobutyric acidB receptor antagonists: stereostructure-activity relationships.

Abstract: The (R) and (S) forms of 5‐amino‐2‐hydroxyvaleric acid (2‐OH‐DAVA) and 5‐amino‐4‐hydroxyvaleric acid (4‐OH‐DAVA) were designed as structural hybrids of the 4‐aminobutyric acidB (GABAB) agonist (R)‐(–)‐4‐amino‐3‐hydroxybutyric acid [(R)‐(–)‐3‐OH‐GABA] and the GABAB antagonist 5‐aminovaleric acid (DAVA). (S)‐(–)‐2‐OH‐DAVA and (R)‐(−)‐4‐OH‐DAVA showed a moderately potent affinity for GABAB receptor sites in rat brain and showed GABAB antagonist effects in a guinea pig ileurn preparation. The respective enantiomers, (R)‐(+)‐2‐OH‐DAVA and (S)‐ (+)‐4‐OH‐DAVA, were markedly weaker in both test systems. AH four compounds were weak inhibitors of GABAA receptor binding in rat brain, and none of them significantly affected synaptosomal GABA uptake. Based on molecular modeling studies it has been demonstrated that low‐energy conformations of (R)‐(–)‐3‐OH‐GABA, (S)(–)‐2‐OH‐DAVA, and (R)‐(–)4‐OH‐DAVA can be superimposed. These conformations may reflect the shapes adopted by these conforma‐tionally flexible compounds during their interaction with GABAB receptors. The present studies emphasize the similar, but distinct, constraints imposed on agonists and antagonists for GABAB receptors.

The non-depolarizing D-form of bromohomoibotenic acid enhances depolarizations evoked by the L-form or quisqualate

The D-enantiomer of bromohomoibotenic acid (Br-HIBO) was inactive in electrophysiological experiments when administered alone, but enhanced depolarizations evoked by L-Br-HIBO or quisqualate when co-administered with these agonists. In addition, quisqualate induced a long-lasting (> 120 min) sensitization of cortical wedge neurons to D-Br-HIBO. This latter effect of D-Br-HIBO was similar to, but significantly more potent and selective, than the earlier observed quisqualate-induced sensitization of cortical neurones to depolarization by (S)-2-amino-4-phosphonobutyric acid (L-AP4).

Enzymatic resolution of AMPA by use of α-chymotrypsin

The enantiomers of AMPA and its diethyl derivative were prepared by an enzymatic resolution using α-chymotrypsin in solution. Electrophysiological studies in vivo and in vitro showed the excitatory effects of AMPA to reside mainly in the L-enantiomer in agreement with the IC50 values of 0.02 μM and 76 μM observed for the L- and D-enantiomer, respectively, in [3H]AMPA binding assays.

Glutamate and aspartate agonists structurally related to ibotenic acid

This mini-review describes a noval class of excitatory heterocyclic amino acid. The selective interactions of these synthetic amino acids with the central glutamic acid (GLU) and aspartic acid (ASP) receptors have been established on the basis of microelectrophoretic techniques using glutamic acid diethyl ester (GDEE) and α-aminoadipic acid (α-AA) as selective antagonists for GLU and ASP, respectively. The parent compound, ibotenic acid (IBO) preferentially activates ASP receptors, but elongation of the side chain of IBO afforded homoibotenic acid (homo-IBO), a GLU agonist. The introduction of bulky substituents into the heterocyclic ring of homo-IBO resulted in a dramatic increase in potency. Alteration of the position of the side chain in IBO to give α-amino-5-methyl-3-hydroxy-4-isoxazoleacetic acid (AMAA), preserved the ASP agonism. However, elongation of the side chain of AMAA gave α-amino-5-methyl-3-hydroxy-4-isoxazolepropionic acid (AMPA), which is a very powerful neuronal excitant with selective interaction with the GLU receptors.

Syntheses of (RS)-homoibotenic acid and (RS)-4-bromohomoibotenic acid. An unusual Michael type reaction and isoxazole deprotection

Addition of ammonia to (E)-3-methoxyisoxazole-5-propenoic acid with concurrent Lewis acid induced deprotection yields (RS)-α-amino-3-hydroxyisoxazole-5-propionic acid (homoibotenic acid), which was independently synthesized by an unambiguous route also used for the preparation of (RS)-α-amino-3-hydroxy-4-bromoisoxazole-5-propionic acid.