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Several potent and selective agonists of the glutamate (L-GLU) receptors of N-methyl-D-aspartate (NMDA) type have been tested on the L-[3H]GLU binding to rat cortical membranes, on the depolarization of mouse cortical wedges and on the contraction of guinea pig longitudinal muscle myenteric plexus preparations with the aim of comparing the NMDA receptors present in the cortex and those present in the gut. When the depolarization of the cortical wedges was evaluated, the EC50 values of the agonists were (microM): (R,S)-(tetrazol-5-yl)-glycine (TG) 0.3; trans-4-hydroxy-(S)-pipecolic acid-4-sulfate (t-HPIS) 0.7; 1-aminocyclobutane-cis-1,3-dicarboxylic acid (ACBD) 0.8; NMDA 8; (2S,3R,4S) cyclopropylglutamate (L-CGA C) 12; quinolinic acid (QUIN) 400. When the contraction of the longitudinal muscle myenteric plexus was evaluated, the EC50 values were (microM): L-CGA C 1; TG 8; ACBD 50; t-HPIS 100; QUIN 500 and NMDA 680. When the displacement of NMDA specific L-[3H]GLU binding from rat cortical membranes was evaluated, the IC50 values were (microM): L-CGA C 0.003; TG 0.005; ACBD 0.044; t-HPIS 0.062; NMDA 0.31 and QUIN 15. No significant correlation was found when the EC50 values obtained in the ileum were plotted against the EC50 values obtained in the cortex (r = 0.47). In particular it was noted that L-CGA C was approximately three orders of magnitude more potent than NMDA when tested in the ileum but had a potency not significantly different from that of NMDA when tested in the cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Enantiomerically pure sulfate esters of the hydroxy amino acids homserine, hydroxyproline and 4-hydroxypipecolic acid were synthesized and tested on α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N- methyl- D -aspartate (NMDA) receptors present in the mice cortical wedge preparation and on NMDA receptors present in the myenteric plexus of the guinea pig with the aim of finding new possible ligands (either agonists) for excitory amino acid receptors. The linear and flexible compound S-homoserine sulfate caused a depolarization of both AMPA and NMDA receptors. In the cortex its agonist action had an EC50 of 150 μM for NMDA and 300 μM for AMPA receptors and in the myenteric plexus its EC50 was 600 μM. The stereoisomer R-homoserine sulfate did not depolarize the cortical wedges and failed to cause ileal contraction up to a concentration of 500 μM. Among the four possible stereoisomers of 4-hydroxyproline sulfate, which are rigid structures and may be regarded as cyclization forms of homoserine sulfate, t-S-hydroxyproline sulfate was a selective AMPA receptor agonist with an EC50 of 70 μM in the cortex. The other three isomers were not active as agonists up to 500 μM and none of them had antagonist activity. Finally, t-4-rmhydroxy-S-pipecolic acid-4-sulfate, a superior homologue of t-S-hydroxyproline sulfate, was found to be one of the most potent and selective NMDA receptor agonists so far described with an EC50 of 0.7 μM in the cortex and 250 μM in the myenteric plexus. The cis-stereoisomer was significantly less potent (EC50 75 μM in the cortex and no activity up to 500 μM in the myenteric plexus). In conclusion, S-homoserine sulfate, t-S-hydroxyproline sulfate and t-4-hydroxy-S-pipecolic acid-4-sulfate are natural compounds able to interact agonists in a stereospecific and selective manner with ionotropic glutamate receptors.

The synthesis of the 2-azabicyclo[3.1.0]hexane derivative 3 together with its transformation into 2-carboxy-4-carboxymethyl-pyrrolidin-5-ol lactone ( 6 ), a useful proline derivative is described.

The dirhodium(II) tetraacetate catalysed reaction of ethyl diazoacetate with 2,3-dihydropyrrole-2,2-dicarboxylate 5 afforded the useful 2-azabicyclo[3.1.0]hexane derivative 6. Its conversion into the proline-γ-acetic acid equivalent 9 as well as into the four isomers constituting the 4-(carboxymethyl)proline 13(16a–19a) whose absolute configuration was established by an alternative asymmetric synthesis of two of them is described. Preliminary data concerning the affinity of compounds 16a–19a for the NMDA site of the NMDA receptor complex are also reported.

A simple and practical synthesis of L-vinylglycine starting from L-homoserine is described.

A convenient procedure for the preparation of L-α-aminoadipic acid from L-glutamic acid is described.

By submitting the ketene silyl acetyl (5a) generated from 3α,7α-dihydroxy-5β-cholan-24-oic acid [chenodeoxycholic acid (1a)], to a variety of oxidants, a new efficient route to (23R)-3α,7α,23-trihydroxy-5β-cholan-24-oic acid [phocaecholic acid, (3a)] and its (23S)-epimer (4a) has been developed. By this route, the first synthesis of 3α,12α,23-trihydroxy-5β-cholan-24-oic acid (bitocholic acid) has been achieved and the stereochemistry at C-23 conclusively assigned as R. Aqueous physical chemical properties of (3a) have been studied and compared with those of (1a) and 3α,7α,12α-trihydroxy-5β-cholan-24-oic acid [cholic acid, (1b)], in order to gain insight into the influence of the hydroxy group at C-23 on the physical properties of bile acids.

A convenient procedure for the preparation of L-α-aminoadipic acid from L-glutamic acid is described.

A simple and practical synthesis of L-vinylglycine starting from L-homoserine is described.

6,6-Dicarboxy-3,4-methano-L-proline (L-DCMP, 7) has been prepared by the rhodium(II)acetate dimer catalyzed decomposition of dimethyl diazomalonate in the presence of a 3,4-didehydroproline derivative. When evaluated against NMDA- and kainate-induced toxicity in cultured cortical neurons, L-DCMP (7) exhibited good neuroprotective activity.