A new preparation of baclofen is proposed. The key step involved a regioselective ring opening of 2-phenylaziridine with allylmagnesium bromide. Further oxydation of the side chain give access to 4-phenyl-pyrrolidin-2-one and to baclofen.

N-Activated 2-phenylazetidines were opened regioselectively at the benzylic carbon with various allylsilanes or propargylsilane in the presence of BF3·Et2O, providing amino olefins, precursors of biomolecules such as phenyl-homo-kainoids.

An efficient preparation of a series of secondary amines, structurally related to the kainic acid scaffold, is described. Naturally occurring (-)-alpha-kainic acid was hydroformylated with complete terminal selectivity and high stereoselectivity. The stereochemistry of the product was investigated through the ROESY and FIETLOC spectra of the corresponding 2,4-dinitrophenyl hydrazone, showing the presence of a single diastereoisomer with rotamers related to the presence of the Boc group. The aldehyde was used as a platform to prepare amines by reductive amination in ionic liquids.

A three-component reaction is described using an aldehyde, a carbamate and trimethylpropargylsilane in the presence of a Lewis acid for the production in moderate to good yield of α-allenyl amines. The reaction is applicable to aromatic or aliphatic aldehydes. The obtained α-aminoallenes are transformed into Δ3-pyrrolidines or amino acids by using the reactivity of the cumulene function.

A general method based on the sequential reactivities of bis-bromocycloalkenes (3–5) is proposed for the preparation of phosphonocycloalkanes (1a/b–3a/b), representing structural constrained analogues of AP4. For the synthesis of an additional congested AP4 analogue (4), an intramolecular cyclopropanation of a ketocarbene towards a vinyphoshonate, assisted by Rh(OAc)2 was successfully experimented.

N-Tosylaziridine (1) and N-tosylazetidine (2) react as 1,3 and 1,4 masked dipoles with electron rich alkenes, respectively, either under kinetic or thermodynamic control. The reactivity of the new aza oxo [4.4.0] 9, a precursor of N-tosyliminium, was exploited for the preparation of stereodefined substituted piperidines.

N-Tosyl-2-phenylazetidine 1 in the presence of BF3. Et2O reacts as a formal 1,4 dipole with various activated or non activated alkenes.

The α,β-unsaturated lactam 3 was submitted to 1,4-addition of organocuprate reagents R2CuLiI2 (R = Me, Bu or Ph) to provide the 4-substituted compounds 5a–c, 6a–c as a mixture of diastereomers; these intermediates were then transformed into the corresponding α-amino-γ-substituted adipic acids 7a–c, 8a–c.

AbstractChemInform 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 important naturally occurring β-amino acid N-Boc-ADDA is prepared following a disconnection of the CC bond between the two E,E double bonds. The stereochemistry of the two synthons was controlled using the alkylation of chiral bromoallenes derived from naturally occurring (S)-serine and (S)-phenyllactic acid. The cupration of bromoallenes derived from (S)-serine also provides a general method for the synthesis of chiral β-alkylated aspartic acid derivatives.

ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXT(2S,4S)-2-Amino-4-(4,4-diphenylbut-1-yl)- pentane-1,5-dioic Acid: A Potent and Selective Antagonist for Metabotropic Glutamate Receptors Negatively Linked to Adenylate CyclaseCamille G. Wermuth, André Mann, Angèle Schoenfelder, Rebecca A. Wright, Bryan G. Johnson, J. Paul Burnett, Nancy G. Mayne, and Darryle D. SchoeppView Author Information UPR 421, Centre de Neurochimie du CNRS, Strasbourg, France, and Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285 Cite this: J. Med. Chem. 1996, 39, 4, 814–816Publication Date (Web):February 16, 1996Publication History Received2 November 1995Published online16 February 1996Published inissue 1 January 1996https://pubs.acs.org/doi/10.1021/jm9508144https://doi.org/10.1021/jm9508144rapid-communicationACS PublicationsCopyright © 1996 American Chemical SocietyRequest reuse permissionsArticle Views352Altmetric-Citations53LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Antagonists,Molecular structure,Monomers,Peptides and proteins,Receptors Get e-Alerts

AbstractChemInform 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.

Nafadotride (N[(n-butyl-2-pyrrolidinyl)methyl]-1-methoxy-4-cyano naphtalene-2-carboxamide) is a novel compound, which inhibits potently and stereoselectively [125I]iodosulpride binding at recombinant human dopamine D3 receptors. the levoisomer displays an apparent Ki value of 0.3 nM at the dopamine D3 receptor, but is 10 times less potent at the human recombinant dopamine D2 receptor. In comparison, the dextroisomer displays 20-fold less apparent affinity at the dopamine D3 receptor and reduced (2-fold) selectivity. l-Nafadotride displays iow, micromolar affinity at dopamine D1 and D4 receptors and negligible apparent affinity at various other receptors. In dopamine D3 receptor-transfected NG-108 15 cells, in which dopamine agonists increase mitogenesis, l-nafadotride has no intrinsic activity, but competitively antagonizes the quinpirole-induced mitogenetic response, monitored by [3H]thymidine incorporation with a pA2 of 9.6. In dopamine D2 receptor-transfected Chinese Hamster Ovary cells, l-nafadotride also behaves as a competitive antagonist of quinpirole-induced mitogenesis with an 11-fold lower potency. These studies establish nafadotride as a pure, extremely potent, competitive and preferential dopamine D3 receptor antagonist in vitro. l-Nafadotride displaces in vivo N-[3H]propylnorapomorphine accumulation at lower dosage and for longer periods in limbic structures, containing both dopamine D2 and D3 receptors than in the stratum, containing dopamine D2 receptor only. At low dosage (0.1-1 mg/kg), nafadotride, unlike haloperidol, a dopamine D2 receptor-preferring antagonist, increases spontaneous locomotion of habituated rats and climbing behavior of mice, at doses that do not modify striatal homovanillic acid levels. At high dosage (1-100 mg/kg), nafadotride, like haloperidol, produces catalepsy and antagonizes apomorphine-induced climbing.(ABSTRACT TRUNCATED AT 250 WORDS)

AbstractChemInform 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.

AbstractChemInform 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.

Potassium cyanide is an efficient catalyst for the alcoholysis of various N-Boc pyroglutamates. The sequence provides a convenient preparation of dissymmetrical α— and γ—glutamate diesters.

Substituted 4-hydroxybutyric (GHB) or trans-4-hydroxycrotonic acids (T-HCA) and structurally related compounds were synthesized and submitted to [3H]GHB binding. Structure-activity relationships studies highlighted for [3H]GHB binding (a) the necessity of a nonlactonic, relatively extended conformation of the gamma-hydroxybutyric chain, (b) the existence of some bulk tolerance in the vicinity of the hydroxyl group, and (c) the high sensitivity toward isosteric replacements of the carboxyl or the hydroxyl groups. T-HCA has been recently identified as a naturally occurring substance in the central nervous system (CNS) and shows a better affinity than GHB. Our findings are in favor of the presence in the CNS of specific GHB binding sites, which are different from the GABA and the picrotoxin binding sites, and for which T-HCA may be an endogenous ligand.

We have recently shown that an arylaminopyridazine derivative of GABA, SR 95103 [2-(3-carboxypropyl)-3-amino-4-methyl-6-phenylpyridazinium chloride], is a selective and competitive GABA-A receptor antagonist. In order to further explore the structural requirements for GABA receptor affinity, we synthesized a series of 38 compounds by attaching various pyridazinic structures to GABA or GABA-like side chains. Most of the compounds displaced [3H]GABA from rat brain membranes. All the active compounds antagonized the GABA-elicited enhancement of [3H]diazepam binding, strongly suggesting that all these compounds are GABA-A receptor antagonists. None of the compounds that displaced [3H]GABA from rat brain membranes interacted with other GABA recognition sites (GABA-B receptor, GABA uptake binding site, glutamate decarboxylase, GABA-transaminase). They did not interact with the Cl- ionophore associated with the GABA-A receptor and did not interact with the benzodiazepine, strychnine, and glutamate binding sites. Thus, these compounds appear to be specific GABA-A receptor antagonists. In terms of structure-activity, it can be concluded that a GABA moiety bearing a positive charge is necessary for optimal GABA-A receptor recognition. Additional binding sites are tolerated only if they are part of a charge-delocalized amidinic or guanidinic system. If this delocalization is achieved by linking a butyric acid moiety to the N(2) nitrogen of a 3-aminopyridazine, GABA-antagonistic character is produced. The highest potency (approximately equal to 250 times bicuculline) was observed when an aromatic pi system, bearing electron-donating substituents, was present on the 6-position of the pyridazine ring.