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At least 739 records · Page 41Linked to original sources
PubMed1977

Azabicycloalkanes as analgetics. 3. Structure-activity relationships of 1-phenyl-6-azabicyclo[3.2.1]octanes and absolute stereochemistry of (+)-1-(3-hydroxyphenyl)-6-methyl-6-azabicyclo[3.2.1]octane and its 7-endo-methyl derivative.

A series of 53 1-phenyl-6-azabicyclo[3.2.1]octanes (1) has been tested for their analgetic and narcotic antagonist activities. Structure-activity relationships were investigated by varying the structural parameters. The most interesting compound in this series, the 1-(3-hydroxphenyl)-6,7-dimethyl derivative 8, shows the profile of a well-balanced antagonist-analgesic agent with a very mild physical dependence capacity. The absolute stereochemistry of its active enantiomer [(+)8] was established by the x-ray study and the chemical transformation to the phenylmorphan [(+)-II]. (+)-8 was stereochemically correlated also with the active enantiomer of the 7-demethyl derivatives [(+)-7] by chemical transformation and CD measurement. Certain structural and stereochemical correlations between these compounds (7 and 8) and other known antagonist-analgetics are discussed.

Analgesics↗
PubMed1987

Synthesis and structure-activity relationships of new muscarinic antagonists.

In an attempt to develop more selective muscarinic acetylcholine receptor (m-AcChR) antagonists, (R)-1-azabicyclo[2.2.2]oct-3-yl-thioxanthene-9-carboxylate, (R,S)-thiochromane-4-carboxylate, and (R,S)-chromane-4-carboxylate were synthesized. Evaluation of the binding affinities of these compounds to muscarinic receptors indicates that replacing the oxygen by sulfur in the xanthenyl and chromanyl moieties does not significantly change selectivity, but does reduce the affinity of 5 and enhance the affinity of 9a.

Animals↗
PubMed2005

Development and biological evaluation of 99mTc-BAT-tropane esters.

Two (99m)Tc-BAT-tropane conjugates, i.e., technetium(V)-oxo-3-[N-(2-mercaptoethyl), N-(N'-(2-mercaptoethyl)-2-aminoethyl)]-aminopropyl 3beta-(4-chlorophenyl)-8-methyl-8-azabicyclo [3.2.1]octane-2beta-carboxylate and the corresponding norchloro derivative, were prepared and evaluated as potential imaging agents for the central nervous dopamine transporter (DAT) system. In these compounds, a tropane and a (99m)Tc-BAT moiety were linked through an ester bond. Both compounds were formed as a mixture of two diastereomers which could be purified and isolated using reversed-phase high-performance liquid chromatography (HPLC). Radio-LC-MS analysis supported the hypothesised structure of the synthesised technetium complexes. After intravenous injection in mice and rats, the compounds were stable in vivo, and no important metabolites were found in plasma or urine. In vitro testing suggested specific competitive binding to the DAT system, but in vivo experiments in rats showed no significant brain uptake for the diastereomers of both compounds; neither was there any specific uptake in the striatum. The results suggest that replacement of a methylene linker by an ester does not seriously affect the binding properties of the tropane conjugates to the dopamine transporter but results in a drastic reduction of passage over the blood-brain barrier (BBB).

Animals↗
PubMed1996

Thermodynamics of 5-HT3 receptor binding discriminates agonistic from antagonistic behaviour.

Thermodynamic parameters delta G degree, delta H degree and delta S degree of the binding equilibrium of eleven ligands (seven agonists and four antagonists) to the serotonin 5-HT3 receptor subtype have been determined by affinity measurements carried out on rat cortex membranes at six different temperatures (0, 10, 20, 25, 30, 35 degrees C) and van't Hoff plots. Affinity constants were obtained from saturation experiments of [3H]endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-methyl-1-H-indazole- 3- carboxamide ([3H]BRL 43694, a selective 5-HT3 ligand) or by its displacement in inhibition assays for the other compounds. Van't Hoff plots were essentially linear in the temperature range investigated, showing that the delta Cp degree of the binding equilibrium is nearly zero. Thermodynamic parameters are in the range 18 < or = delta H degree < or = 53 kJ mol-1 and 202 < or = delta S degree < or = 320 J K-1 mol-1 for agonists and -16 < or = delta H degree < or = 0 kJ mol-1 and 70 < or = delta S degree < or = 179 J K-1 mol-1 for antagonists indicating that agonistic binding is totally entropy-driven while antagonistic binding is relatively less entropy- and more enthalpy-driven in the -T delta S degree versus delta H degree plot the thermodynamic data are clearly arranged in separate clusters for agonists and antagonists, which, therefore, turn out to be thermodynamically discriminated. Experimental results are discussed according to the following main points: (i) the approximate linearity of the delta H degree versus delta S degree plot in terms of enthalpy-entropy compensation and (ii) the fact that delta Cp degree approximately equal to 0 for practically all membrane receptors at variance with most reactions involving biomacromolecules in solution. Finally, the phenomenon of thermodynamical discrimination is reviewed and found to occur in five distinct membrane receptorial systems.

Animals↗
PubMed2000

SB-219383, a novel tyrosyl tRNA synthetase inhibitor from a Micromonospora sp. II. Structure determination.

A novel tyrosyl tRNA synthetase inhibitor, SB-219383, has been isolated from a Micromonospora sp. The structure of SB-219383 has been elucidated by a combination of derivatisation, spectroscopic and other analytical techniques and found to be N-(L-tyrosyl)-2-amino[1(S*),3(S*),4(S*),5(R*),8(R*)-2,4,5,8-tetrahydroxy -7-oxa-2-azabicyclo[3.2.1]oct-3-y1]acetic acid (1).

Bridged Bicyclo Compounds, Heterocyclic↗
PubMed2000

Resin activation capture technology: libraries from stabilized acyl-pyridinium on solid support.

REsin Activation/Capture APproach or REACAP Technology, a novel approach to the synthesis of compound libraries, capitalizes on the formation and retention of a resin-bound reactive intermediate, which can be subsequently transformed into a stable, covalently attached molecule. Any unreacted "reactive intermediate" is quenched and removed from the resin upon work-up, leaving only the desired product on the solid support. In contrast to more traditional solid-supported chemistry that must address issues such as resin-loading, capping of unreactive functionalized moieties, and reaction yields, REACAP offers an attractive alternative with the focus more on the purity of the released products and less on yield. In an endeavor to generate truly non-peptide leads, we describe herein the synthesis of N-acyl-2-substituted-dihydro-4-pyridones, dihydro-4-pyridones, 4-ketopiperidines, tetrahydropyridines, and 2-acyl-3,7,8-substituted-5-oxo-2-azabicyclo[2.2.2]octane and triaza analogs using REACAP Technology.

Databases as Topic↗