AbstractFor Abstract see ChemInform Abstract in Full Text.

Regioselective rapid analogue syntheses of 1-methyl-3,5-diarylpyrazoles were developed, based on Pd-catalysed couplings to 1-methyl-3(5)-arylpyrazole nonaflates, which offered an advantage in hydrolytic stability over the corresponding triflates. The new bifunctional reagent 1-methyl-3-bromo-pyrazol-5-yl nonaflate underwent highly chemoselective Pd-catalysed couplings to the nonaflate, followed by Suzuki couplings to the bromide, allowing sequential, regioselective introduction of the two aryl substituents.

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.

A series of 3-(4-piperidinyl)- and 3-(8-aza-bicyclo[3.2.1]oct-3-yl)-2-phenyl-1H-indoles have been prepared and evaluated as ligands for the h5-HT2A receptor. 3-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-phenyl-1H-indole is a high-affinity (1.2nM), selective (>800 fold over h5-HT2C and hD2 receptors) antagonist at the h5-HT2A receptor with oral bioavailability in rats.

A series of 4-hydroxy-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl] piperidines was investigated as potential selective h5-HT1D agonists for the treatment of migraine. The 4-[(N-benzyl-N-methyl)amino]methyl analog 12a was found to be a full agonist at the h5-HT1D receptor with good binding selectivity over the h5-HT1B receptor.

Two novel series of 3-(heterocyclylmethyl)pyrazoles have been synthesised and evaluated as ligands for the human dopamine D4 receptor. Compounds in series I (exemplified by 8k) have a phenyl ring joined to the 4-position of the pyrazole while those in series II (exemplified by 15j) have a 5-phenyl ring linked by a saturated chain to the 4-position of the pyrazole. Both series supplied compounds with excellent affinity for the human D4 and good selectivity over other dopamine receptors. Excellent selectivity over calcium, sodium, and potassium ion channels was also achieved.

Recent knowledge that replacement of the CS-phenyl group in a series of 1,4-benzodiazepines by CS-aza(bi)cycloalkyl groups gave high affinity, selective, water-soluble CCKB/gastrin receptor antagonists has been extended to the CCKA receptor subtype. This communication describes the synthesis and in vitro biological profile of L-743,345 (3S-N-(3-azabicyclo[3.2.2.]nonan-3-yl-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide), a selective and high affinity ligand for the CCKA receptor. Single crystal x-ray crystallography confirmed the absolute configuration to be 3S, the same as Devazepide.

L'invention concerne un compose de la formule (I), un sel ou un precurseur de celui-ci. Dans cette formule E, G, Q, R1, T, U, V et Z et Z sont tels que definis dans la description. Ces composes sont des agonistes actifs des recepteurs du type 5-HT?1?. L'invention concerne egalement des procedes pour preparer ces composes, des preparations pharmaceutiques les contenant et leur utilisation therapeutique.

A novel series of potent, water-soluble benzodiazepine based CCKB/gastrin antagonists has been prepared which incorporate an N-methylpiperazine group at the C5 position of the benzodiazepine ring system. The N1-n-propyl analogue (7b) is a high affinity, selective and potent receptor antagonist in vitro, with good bioavailability and excellent oral absorption providing high plasma levels in vivo.

A novel series of 5-amino-1,4-benzodiazepin-2-one derivatives (amidines), which contain a cationic solubilizing group and which are antagonists for the cholecystokinin (CCK)-B receptor, have been identified. Optimization of this series led to the identification of an azabicyclononane amidine, L-740,093 [N-[(3R)-5-(3-azabicyclo[3.2.2]nonan-3-yl)-2,3-dihydro-1-methyl-2- oxo- 1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea], that bound with high affinity of CCK-B receptors from guinea pig cerebral cortex (IC50 of 0.1 nM) and had a CCK-B/CCK-A receptor selectivity of 16,000. In comparison, L-365,260 had 85-fold lower affinity (8.5 nM) and was only 87-fold selective for CCK-B over CCK-A receptors. L-740,093 bound with high affinity to guinea pig gastrin receptors in vitro (IC50 of 0.04 nM). Electrophysiological studies on slices of rat ventromedial hypothalamic nucleus showed that L-740,093 produced rightward shifts of the concentration-response curve for the CCK-B receptor agonist pentagastrin (Kb of 0.06 nM). L-740,093 blocked pentagastrin-induced gastric acid secretion in anesthetized rats with a 50% inhibitory dose of 0.01 mg/kg, intraperitoneally, showing 100-fold greater activity, compared with L-365,260 (50% inhibitory dose of 1 mg/kg, intraperitoneally). An ex vivo binding assay in mice was used to investigate the interaction of L-740,093 with central CCK binding sites. After intravenous administration, L-740,093 inhibited ex vivo binding dose dependently, with a 50% effective dose of 0.2 mg/kg. These studies demonstrate that L-740,093 is the most potent and selective CCK-B antagonist yet described and that it has excellent central nervous system penetration.

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.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTHigh-Affinity and Potent, Water-Soluble 5-Amino-1,4-benzodiazepine CCKB/Gastrin Receptor Antagonists Containing a Cationic Solubilizing GroupGraham A. Showell, Sylvie Bourrain, Joseph G. Neduvelil, Stephen R. Fletcher, Raymond Baker, Alan P. Watt, Alan E. Fletcher, Stephen B. Freedman, John A. Kemp, and Cite this: J. Med. Chem. 1994, 37, 6, 719–721Publication Date (Print):March 1, 1994Publication History Published online1 May 2002Published inissue 1 March 1994https://pubs.acs.org/doi/10.1021/jm00032a002https://doi.org/10.1021/jm00032a002research-articleACS PublicationsRequest reuse permissionsArticle Views226Altmetric-Citations52LEARN 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 Get e-Alerts