Carlo De Micheli

• Professor
• University of Milan

Natural and synthetic electrophilic compounds have been shown to activate the antioxidant protective Nrf2 (nuclear factor erythroid 2‐related factor 2)/heme oxygenase‐1 (HO‐1) axis in cells and tissues. Here, we tested the ability of different isoxazoline‐based electrophiles to up‐regulate Nrf2/HO‐1. The potency of activation is dependent on the le...

Natural and synthetic electrophilic compounds have been shown to activate the antioxidant protective Nrf2 (nuclear factor erythroid 2‐related factor 2)/heme oxygenase‐1 (HO‐1) axis in cells and tissues. Here, we tested the ability of different isoxazoline‐based electrophiles to up‐regulate Nrf2/HO‐1. The potency of activation is dependent on the le...

Trypanosoma brucei (T. brucei) is the agent of Human African Trypanosomiasis (HAT), a neglected disease that threats the life of 65 million people in sub Saharan Africa every year. Unfortunately, available therapy is unsatisfactory, mainly due to safety issues and developing resistances. Significant efforts over the last decades have been made in th...

The lipase-catalyzed regioselective hydrolysis of peracetylated arabinose was performed in a packed bed flow reactor (PBR). In particular, the hydrolysis of the α anomer of peracetylated arabinose catalyzed by Novozym® 435 resulted in the monodeprotection of C5 in only 5 min and 91% yield. By using the immobilized Pseudomonas stutzeri lipase, the r...

The synthesis of analogues of the natural compound l-tricholomic acid and of its threo diastereoisomer was accomplished in order to explore their affinity for glutamate ionotropic receptors. In this study, fourteen new unnatural amino acids, characterized by a 3-hydroxy-▵2-isoxazoline or 3-hydroxy-▵2-pyrazoline-skeleton, were obtained exploiting, a...

Significance Despite decades of studies, the development of competitive glutamate-site antagonists that can distinguish between NMDA receptor subtypes based on GluN2 subunits has been unsuccessful. The resulting lack of subunit-selective NMDA receptor ligands has led to the widespread use of competitive antagonists with only modest subunit preferen...

The chemoenzymatic flow synthesis of enantiomerically pure captopril, a widely used antihypertensive drug, is accomplished starting from simple, inexpensive, and readily available reagents. The first step is a heterogeneous biocatalyzed regio- and stereoselective oxidation of cheap prochiral 2-methyl-1,3-propandiol, performed in flow using immobili...

Abnormal activity of various N-methyl-D-aspartate receptor (NMDAR) subtypes has been implicated in a wide variety of neurological disorders such as Alzheimer’s disease, schizophrenia and epilepsy. Imaging agents for PET and SPECT that target NMDARs in a subtype-selective fashion may enable better characterization of those disorders and enhance drug...

γ-Glutamyl-dipeptides, built by condensing the distal carboxylate of l-Glu (or d-Glu) onto a series of differently functionalized amino acids, were prepared and used as tools for rapidly probing the stereo-electronic properties of iGluRs, searching for subtype-selective ligands.

Homologation of glutamic acid chain together with conformational constraint is a commonly used strategy to achieve selectivity towards different types of glutamate receptors. In the present work, starting from two potent and selective unnatural amino acids previously developed by us, we investigated the effects on the activity/selectivity profile p...

Compounds based on the 3-Br-isoxazoline scaffold fully inhibit glyceraldehyde 3-phosphate dehydrogenase from Plasmodium falciparum by selectively alkylating all four catalytic cysteines of the tetramer. Here, we show that, under the same experimental conditions that led to a fast and complete inhibition of the protozoan enzyme, the human ortholog w...

Over the past few decades, there has been an increasing interest in the development of covalent enzyme inhibitors. As it was recently re-emphasized, the selective, covalent binding of a drug to the desired target can increase efficiency and lower the inhibitor concentration required to achieve a therapeutic effect. In this context, the naturally oc...

Novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation were developed; some of them possess Ki values in the micromolar range. We studied the structure-activity relationship of these derivatives and we performed docking studies, which allowed us to find out the key interactions established...

The bifunctional enzyme N5,N10-methylenetetrahydrofolate dehydrogenase/cyclo hydrolase (FolD) is essential for growth in Trypanosomatidae. We sought to develop inhibitors of Trypanosoma brucei FolD (TbFolD) as potential antiparasitic agents. Compound 2 was synthesized, and the molecular structure was unequivocally assigned through X-ray crystallogr...

New unconventional beta and gamma dipeptides, representing conformational constrained higher homologues of glutamic acid, have been prepared and tested as new pharmacological tools to investigate the iGluR binding domain, in the attempt to identify potential selective antagonists.

Nicotinic acetylcholine receptors (nAChRs) play an important role in many central nervous system disorders such as Alzheimer's and Parkinson's diseases, schizophrenia, and mood disorders. The α4 β2 subtype has emerged as an important target for the early diagnosis and amelioration of Alzheimer's disease symptoms. Herein we report a new class of α4...

The γ-aminobutyrate (GABA)-degradative enzyme GABA aminotransferase (GABA-AT) is regarded as an attractive target to control GABA levels in the central nervous system: this has important implications in the treatment of several neurological disorders and drug dependencies. We have investigated the ability of newly synthesized compounds to act as GA...

We developed a new class of covalent inhibitors for Plasmodium falciparum glyceraldehyde-3-phosphate dehydrogenase, a validated target for the treatment of malaria, by screening a small library of 3-bromo-isoxazoline derivatives that inactivate the enzyme through a covalent, selective bond to the catalytic cysteine, as demonstrated by mass spectrom...

Novel papain-family cathepsin L-like cysteine protease inhibitors endowed with antitrypanosomal and antimalarial activity were developed, through an optimization study of previously developed inhibitors. In the present work, we studied the structure-activity relationships of these derivatives, with the aim to develop new analogues with a simplified...

A convenient synthesis of four new enantiomerically pure acidic amino acids is reported and their affinity at ionotropic glutamate receptors was determined. The new compounds are higher homologues of glutamic acid in which the molecular complexity has been increased by introducing an aromatic/heteroaromatic ring, that is a phenyl or a thiophene rin...

Novel rhodesain inhibitors were obtained by combining an enantiomerically pure 3-bromoisoxazoline warhead with a specific peptidomimetic recognition moiety. All derivatives behaved as inhibitors of rhodesain, with low micromolar Ki values. Their activity against the enzyme was found to be paralleled by an in vitro antitrypanosomal activity, with IC...

The present paper deals with an improved synthesis of two molecular hybrids of AMPA and KA, compounds CIP-A and CIP-B, and their transformation into CIOP-A and CIOP-B, the corresponding amido derivatives. Exploiting the continuous-flow technology, a significant improvement in the synthesis of the glutamate agonists CIP-A and CIP-B was accomplished,...

A synthetic method for the preparation of suitably protected 3-carboxy-Δ(2)-pyrazolin-5-yl-alanine was developed. This scaffold is amenable to further decoration at the N1 position and was used to generate novel NMDA receptor ligands. Although weaker than the previously reported N1-Ph derivatives, the new ligands retain the ability to selectively b...

Rhodesain, a cathepsin L-like cysteine protease of T. brucei rhodesiense, is considered a potential target for the treatment of Human African Trypanosomiasis. Recent findings have confirmed that rhodesain, a lysosomal protease, is essential for parasite survival. Rhodesain is required by T. brucei to cross the blood-brain barrier, degrade host immu...

Falcipain-2 (FP-2) is a papain-family cysteine protease of Plasmodium falciparum whose primary function is to degrade the host red cell hemoglobin, within the food vacuole, in order to provide free amino acids for parasite protein synthesis. Additionally it promotes host cell rupture by cleaving the skeletal proteins of the erythrocyte membrane. Th...

A group of spirocyclic tropanyl-Δ(2)-isoxazolines was synthesized exploiting the 1,3-dipolar cycloaddition of nitrile oxides to olefins. Their interaction with the dopamine and serotonin transporters (DAT and SERT, respectively) was evaluated through binding experiments. The majority of the compounds had no inhibitory effects (IC(50) > 10μM), while...

Acivicin analogues with an increased affinity for CTP synthetase (CTPS) were designed as potential new trypanocidal agents. The inhibitory activity against CTPS can be improved by increasing molecular complexity, by inserting groups able to establish additional interactions with the binding pocket of the enzyme. This strategy has been pursued with...

Epiboxidine hydrochlorides (+)-2 and (-)-2, which are the structural analogs of the antipodes of epibatidine (±)-1, as well as the enantiomeric pairs (+)-3/(-)-3 and (+)-4/(-)-4 were synthesized and tested for binding affinity at α4β2 and α7 nicotinic acetylcholine receptor (nAChR) subtypes. Final derivatives were prepared through the condensation...

Glutamate transporters play an important role in the regulation of extracellular glutamate concentrations in the mammalian brain and are, thus, promising targets for therapeutics. Despite this importance, the development of pharmacological tools has mainly focused on the synthesis of competitive inhibitors, which are amino acid analogues that bind...

A derivative of the malonic semialdehyde was transformed by means of a bioconversion catalyzed by the enzyme L-threonine aldolase from E. coli into a 6:4 epimeric mixture of two precursors of β-hydroxy glutamic acid. The enzyme was selective for the formation of the (S)–configuration at C-2, whereas the configuration at C-3 was not controlled. The...

A set of structural analogues of spirocyclic quinuclidinyl-Δ(2)-isoxazolines, characterized as potent and selective α7 nicotinic agonists, was prepared and assayed for binding affinity at α7 and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs). The investigated derivatives (3a-3c, 4a-4c, 5a-5c, 6a-6c, and 7a-7c), synthesized via the 1,3-dip...

A homeostatic concentration of glutamate in the synaptic cleft ensures a correct signal transduction along the neuronal network. An unbalance in this concentration can lead to neuronal death and to severe neurodegenerative diseases such as Alzheimer's or Parkinson's. Glutamate transporters play a crucial role in this respect because they are respon...

The classification of racemases, their diffusion, function, localization, structural features and the state of the art in the discovery of novel drugs targeting such enzymes for the treatment of different pathologies, is discussed. The biological activity of the peptides is found to be strictly dependent, not only on the presence of D-amino acids,...

α6β2* Nicotinic acetylcholine receptors are expressed in selected central nervous system areas, where they are involved in striatal dopamine (DA) release and its behavioral consequences, and other still uncharacterized brain activities. α6β2* receptors are selectively blocked by the α-conotoxins MII and PIA, which bear a characteristic N-terminal a...

Two highly versatile isoxazoline derivatives, as key in-termediates for the synthesis of differently functionalized subtype-selective N-methyl-D-aspartate receptor antagonists, were designed and synthesized. The synthetic strategy is based on an intramolecu- lar nitrile oxide cycloaddition reaction which is a powerful method capable of controlling...

A set of racemic spirocyclic quinuclidinyl-Δ(2)-isoxazoline derivatives was synthesized using a 1,3-dipolar cycloaddition-based approach. Target compounds were assayed for binding affinity toward rat neuronal homomeric (α7) and heteromeric (α4β2) nicotinic acetylcholine receptors. Δ(2) -Isoxazolines 3 a (3-Br), 6 a (3-OMe), 5 a (3-Ph), 8 a (3-OnPr)...

The synthesis of four new isoxazoline-based amino acids being analogues of previously described glutamate receptor ligands is reported and their affinity for ionotropic glutamate receptors is analyzed in comparison with that of selected model compounds. Molecular modelling investigations have been carried out to rationalize the interaction with the...

The first convenient synthesis of enantiomerically pure (αS,5S)-α-amino-3-bromo-4,5-dihydroisoxazol-5-yl acetic acid (3-bromoacivicin) is described. We demonstrate that 3-bromoacivicin is a CTP synthetase inhibitor three times as potent as its 3-chloro analogue, the natural antibiotic acivicin. Because CTP synthetase was suggested to be a potential...

The chemoenzymatic approach to the preparation of some chiral biologically active heterocycles is discussed. Synthetic strategies took advantage of enantioselective bioconversion processes carried out on suitable reaction intermediates. Reductions of carbonyl compounds catalyzed by different alcohol dehydogenases (TBADH from Thermoanaerobium brocki...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The design and synthesis of new N1-substituted 3-carboxy- and 3-phosphonopyrazoline and pyrazole amino acids that target the glutamate binding site of NMDA receptors are described. An analysis of the stereochemical requirements for high-affinity interaction with these receptors was performed. We identified two highly potent and selective competitiv...

A series of isoxazole-based histone deacetylase (HDAC) inhibitors structurally related to SAHA were designed and synthesized. The isoxazole moiety was inserted in the vicinity of the Zn(2+)-binding group in order to check its participation in the coordinating process.

The enantiopure diastereomeric Δ2-isoxazoline derivatives (2S,5'R)-5a-10a and (2S,5'S)-5b, (2S,5'S)-9b, (2S,5'S)-11b, which are structural analogues of both ABT-418 2 and oxyimino ethers (S)-3 and (Z)-(S)-4, were synthesized through cycloaddition reactions involving nitrile oxides as 1,3-dipoles and (S)-N-Boc-2-vinylpyrrolidine-13 as the dipolaroph...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The two pairs of enantiomers of isoxazolidin-3-ones 3 and 4 were synthesized by means of Lipase PS-catalyzed hydrolyses of suitable racemic butyrates. The same butyrates were also employed as key intermediates in the preparation of racemic 3 and 4. The antimuscarinic potency of the new compounds was assayed in two in vitro functional tests. The eut...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The synthesis of the two pairs of enantiomers of methylenemuscarones 3 and 4 has been accomplished by using (R)- and (S)-lactic esters as starting materials. Due to the existence of different muscarinic receptor subtypes, the compounds were examined for their ability to bind membranes from cerebral cortex (M1), heart (M2), and salivary glands (M3)...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The multi-step preparation of N-Boc-3,4-dehydro-L-proline methyl ester using a modular flow reactor is reported. The use of immobilised reagents and scavengers in pre-packed glass tubes allows us to obtain the pure product in 87% overall yield, 97% purity, and >98% enantiomeric excess without any additional purification step. Our flow-based protoco...

IntroductionGeneralCycloadditions of Allyl and Hetero-allyl Anion SystemsCycloadditions of 1,3-Dipoles with an Orthogonal Double BondCycloadditions of 1,3-Dipoles Without an Orthogonal Double BondAcknowledgementsReferences

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A strategy based on the use of (R)- and (S)-lactic ester as starting materials allowed the synthesis of the two enantiomers of muscarone [(-)-1 and (+)-1] and allomuscarone [(-)-5 and (+)-5] in greater than 98% enantiomeric excess. The compounds were examined for their ability to bind to membranes from cerebral cortex (M1), heart (M2), and salivary...

An efficient stereoselective preparation of the two enantiomerically pure diasteroisomers of γ-benzyloxy-S-glutamic acid was performed using trans-4-hydroxy-l-proline as a source of chirality, while the erythro and threo isomers of β-benzyloxy-S-glutamic acid were prepared starting from (R)-Garner's aldehyde. All new derivatives were tested for the...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

This report describes an efficient synthesis of the natural isomer of acivicin, which is the only one provided with a noteworthy biological activity. The present procedure allowed the synthesis of (+)-1 in just five steps with a 34% overall yield. Due to the easy separation of the two diastereomers and to the availability of the starting material a...

5-Substituted 3-(diethoxyphosphoryl)isoxazoles and -2-isoxazolines were synthesized regioselectively by 1,3-dipolar cycloaddition of(diethoxyphosphoryl)formonitrile oxide to monosubstituted alkynes and alkenes. By applying this methodology to an N-(tert-butoxycarbonyl)-substituted allylglycine methyl ester, we prepared the precursors of two diaster...

A group of agonists for the alpha7 neuronal nicotinic acetylcholine receptors (nAChRs) was investigated, and their free energies of binding DeltaG(bind) were calculated by applying the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) approach. This method, based on molecular dynamics simulations of fully solvated protein-ligand complexe...

(+/-)-3-Hydroxy-4,5,6,6a-tetrahydro-3aH-pyrrolo [3,4 -d]-isoxazole-4-carboxylic acid (HIP-A) and (+/-)-3-hydroxy-4,5,6, 6a-tetrahydro-3aH-pyrrolo[3,4-d]isoxazole-6-carboxylic acid (HIP-B) are selective inhibitors of excitatory amino acid transporters (EAATs), as potent as DL-threo-beta-benzyloxyaspartic acid (TBOA). We report here that the active i...

The two enantiomeric pairs of erythro- and threo-amino-(3'-hydroxy-4',5'-dihydro-isoxazol-5'-yl)-acetic acids were synthesized via the 1,3-dipolar cycloaddition of bromonitrile oxide to ( R)- or ( S)-3-( tert-butoxycarbonyl)-2,2-dimethyl-4-vinyloxazolidine. The pharmacological profiles of the studied amino acids reflect the relationship between the...

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 ‘ami...

The present report deals with the synthesis of the two couples of enantiomers (+)-(3aS,4R,6aS)-/(−)-(3aR,4S,6aR)-3-hydroxy-3a,4,6,6a-tetrahydro-pyrrolo[3,4-d]isoxazole-4-carboxylic acid [(+)-HIP-A and (−)-HIP-A] and (+)-(3aS,6S,6aS)-/(−)-(3aR,6R,6aR)-3-hydroxy-3a,4,6,6a-tetrahydro-pyrrolo[3,4-d]isoxazole-6-carboxylic acid [(+)-HIP-B and (−)-HIP-B],...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A set of novel heterocyclic ligands (6-27) structurally related to Oxotremorine 2 was designed, synthesized and tested at muscarinic receptor subtypes (mAChRs). In the binding experiments at cloned human receptors (hm1-5), compounds 7 and 15 evidenced a remarkable affinity and selectivity for the hm2 subtype. The in vitro functional assays, perform...

Homologation of the glutamic acid chain together with conformational constraint is a commonly used strategy to achieve selectivity towards different types of glutamate receptors. We investigated the effects of a further increase in the distance between the amino acid moiety and the distal carboxylate group of model compounds (+/-)-1 and (+/-)-2 on...

The regioselective synthesis of 5-substituted-3-dimethoxyphosphono-pyrazoles and -2-pyrazolines has been accomplished through the 1,3-dipolar cycloaddition of a suitable nitrile imine to monosubstituted alkynes and alkenes. Examples of hydrolysis of the heterocyclic phosphonic esters to the corresponding acids are described. (c) 2007 Elsevier Ltd....

Twelve novel conformationally constrained homologues of glutamic acid have been synthesized and pharmacologically characterized at ionotropic glutamate receptors (iGluRs). Synthesis of the target compounds involved 1,3-dipolar cycloaddition of nitrile oxides to suitable dipolarophiles. The structure to the compounds has been assigned by (1)H NMR an...

An alternative synthesis of 4-amino-3-hydroxy-4,5,6, 6a-tetrahydro-3aH-cyclopenta[d]isoxazole-4-carboxylic acid, a conformationally constrained analogue of aspartic acid, is described. The synthetic strategy is based on a regioselective 1,3-dipolar cycloaddition to give the cyclopenta[d]isoxazoline framework; subsequent condensation of this 4-oxocy...

Isoxazole derivative (+/-)-4 and the three pairs of stereoisomeric 3-bromo-isoxazolyl amino alcohols (S,R)-(-)-7a/(R,R)-(+)-7b, (S,R)-(-)-8a/(R,R)-(+)-8b, and (S,R)-(-)-9a/(R,R)-(+)-9b were synthesized and assayed for their affinity and efficacy at human beta(1)-, beta(2)-, and beta(3)-adrenergic receptors (beta-ARs) in membranes from Chinese hamst...

The erythro- and threo-amino-(3'-hydroxy-4',5'-dihydro-isoxazol-5'-yl)-acetic acids, stereoisomers of tricholomic acid, were synthesized along with the corresponding higher homologues erythro- and threo-amino-(3'-carboxy-4',5'-dihydro-isoxazol-5'-yl)-acetic acids. The target compounds were prepared via the 1,3-dipolar cycloaddition of a suitable ni...

A series of 3-hydroxy- and 3-carboxy-Delta(2)-isoxazoline amino acids, structurally related to the GABA(A) agonist THIP and to the GABA uptake inhibitors THPO and exo-THPO, was prepared by means of synthetic strategies involving the 1,3-dipolar cycloaddition of nitrile oxides. All derivatives were submitted to a pharmacological investigation at bot...

The group of Δ2-isoxazoline derivatives 5a–c and 6a–c, structurally related to epibatidine, and the simplified analogues 7a–c were synthesized by means of a 1,3-dipolar cycloaddition-based strategy and tested at α4β2 and α7 neuronal acetylcholine receptor (nAChR) subtypes. Competition binding experiments at α4β2 nAChR subtypes showed an overall sig...

The new enantiomerically pure 3-substituted-Delta(2)-isoxazolin-5-yl-ethanolamines (+)-6a/(-)-6b, (-)-6a/(+)-6b, and (+)-7a/(-)-7b, prepared via a 1,3-dipolar cycloaddition-based approach, were tested for their affinity at human beta(1)-, beta(2)-, and beta(3)-adrenergic receptor (beta-AR) subtypes stably expressed in CHO cells. The corresponding 3...

The Δ2-isoxazoline derivatives 3a-c and 4a-c, structurally related to epibatidine, and the simplified analogues 5a-c were synthesized by means of a 1,3-dipolar cycloaddition of regioisomeric pyridinenitrile oxides to suitable dipolarophiles. Target compounds were assayed at α4β2 and α7 neuronal acetylcholine receptor (nAChR) subtypes. Competition b...

A series of 1-aryl-3,5-dihydro-7,8-ethylenedioxy-4H-2,3-benzodiazepin-4-ones 2a-f, were synthesized and screened as anticonvulsant agents in DBA/2 mice against sound-induced seizures. The new compounds display anticonvulsant properties although the ED(50) values are higher than those of prototypes 1-aryl-3,5-dihydro-7,8-methylenedioxy-4H-2,3-benzod...

The four stereoisomers of 5-(2-amino-2-carboxyethyl)-4,5-dihydroisoxazole-3-carboxylic acid(+)-4, (-)-4, (+)-5, and (-)-5 were prepared by stereoselective synthesis of two pairs of enantiomers, which were subsequently resolved by enzymatic procedures. These four stereoisomers and the four stereoisomers of the bicyclic analogue 5-amino-4,5,6,6a-tetr...

NR2 subunits of N-methyl-d-aspartic acid (NMDA) receptors are known to bind the neurotransmitter glutamate, competitive agonists, and antagonists. Since crystallographic data of these proteins are not available, we built a homology model of the ligand binding domain of the NR2A subunit. A consensus binding mode of selected AP5-like NMDA antagonists...

The two diastereomeric pairs of acidic amino acids 5-(2-amino-2-carboxyethyl)-4,5-dihydroisoxazole-3-carboxylic acid (8A/8B) and 4-(2-amino-2-carboxyethyl)-5,5-dimethyl-4,5-dihydroisoxazole-3-carboxylic acid (10A/10B) were prepared via a strategy based on a 1,3-dipolar cycloaddition. The four amino acids were tested at ionotropic and metabotropic g...

The two enantiomeric pairs of bicyclic isoxazoline acidic amino acids, designed as conformationally constrained homologues of glutamic acid, have been prepared by taking advantage of a nitrile oxide cycloaddition coupled to highly selective biocatalyzed transformations. All four isomeric target amino acids were obtained with enantiomeric excesses h...

We characterized the interaction of two conformationally constrained aspartate and glutamate analogs, 3-hydroxy-4,5,6,6-atetrahydro-3aH-pyrrolo[3,4-d]isoxazole-4-carboxylic acid (HIP-A) and 3-hydroxy-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]isoxazole-6-carboxylic acid (HIP-B), with excitatory amino acid transporters (EAATs) in rat brain cortex synapto...

A series of 1-substituted 2-[(4-aryl)-methyl]-4,5-methylenedioxybenzene derivatives (13-25), structurally related to model compound 5 (2-[(4-aminophenyl)-(4-methylsemicarbazono)-methyl]-4,5-methylenedioxyphenylacetic acid methyl ester), were synthesized and tested as anticonvulsant agents in DBA/2 mice against sound-induced seizures. The new compou...

For Abstract see ChemInform Abstract in Full Text.

5-(4-Aminobenzyl)-7,9-dihydro-8H-[1,3]dioxolo[4,5-h][2,3] benzodiazepin-8-one (3) and 7,9-dihydro-5-[2-(pyridin-2-yl)-vinyl]-8H-[1,3]dioxolo[4,5-h][2,3] benzodiazepin-8-one (4) were synthesized and screened as anticonvulsant agents in DBA/2 mice against sound-induced seizures. The new compounds are provided with anticonvulsant properties even if ED...

A set of novel 1-aryl-6,7-methylenedioxy-3H-quinazolin-4-(thi)ones (3a-f) has been designed and screened as anticonvulsant agents in DBA/2 mice. The new compounds are provided with anticonvulsant properties comparable to those of GYKI 52466. To clarify the mode of action, their affinity for the quinazolinone/2,3-benzodiazepine site of the AMPA rece...

We have prepared four isomeric 3-hydroxycyclopentaisoxazoline amino acids 12-15, which represent analogues of glutamic acid having restricted conformations, through a strategy based on the 1,3-dipolar cycloaddition of bromonitrile oxide to a suitably protected 1-aminocyclopent-2-enecarboxylic acid. These target compounds proved to be inactive when...