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At least 109 records · Page 6Linked to original sources
PubMed2006

3-Aza-6,8-dioxabicyclo[3.2.1]octanes as new enantiopure heteroatom-rich tropane-like ligands of human dopamine transporter.

CNS diseases such as Parkinson, schizophrenia, and attention deficit hyperactivity disorder (ADHD) are characterized by a significant alteration of dopamine transporter (DAT) density. Thus, the development of compounds that are able to selectively interact with DAT is of great interest. Herein we describe the design and synthesis of a new set of 3-aza-6,8-dioxabicyclo[3.2.1]octanes having a tropane-like structure with additional heteroatoms at positions 3 and 6. The compounds were evaluated for their in vitro receptor binding properties toward human dopamine (hDAT) and serotonin (hSERT) transporters using [3H]WIN35,428 and [3H]citalopram as specific radioligands, respectively. Biological assays revealed that some compounds having the N-3 atom substituted with aryl groups possess significant affinity and selectivity for monoamine transporters, and in particular, compound 5d displayed an IC50 of 21 nM toward DAT, and a good selectivity toward SERT (IC50=1042 nM). These results suggest that 3-aryl-3-aza-6,8-dioxabicyclo[3.2.1]octanes may represent a new class of DAT ligands.

Animals↗
PubMed2003

Adsorption of hydrophobically modified polyelectrolytes at the n-octane/water interface.

The interfacial activity of polyelectrolytes carrying alkyl side chains of different length has been studied. Potassium salts of poly(maleic acid-co-1-olefins), PA-n K2 with n=12 , 14, 16, 18, were synthesized, and the interfacial tension at the aqueous solution/n -octane interface was measured as a function of the length of the alkyl side chain. The results show that the interfacial tension lowering, the limiting excess concentration Gamma (m), and the efficiency of adsorption pC (20) depend on the number of methylene groups in the alkyl side chain. According to Rosen the last two parameters define two different contributions to the standard free energy of adsorption: one arises from the distribution of the polymer between the bulk of the solution and the interface Delta G (dist )(0), and another comes from the configuration adopted at the interface Delta G (int )(0). These free energies were plotted as a function of the number of carbon atoms in the alkyl side chain and a linear relation was found for both of them. From these plots contributions of 0.83 and -0.58 per methylene group were determined for Delta G (0)(dist ) and Delta G (0)(int ), respectively. The positive value for the incremental free energy of distribution is attributed to the formation of a polymer micelle which is stabilized by longer alkyl side chains. On the other hand, the negative value for Delta G (0)(int ) indicates that at the interface the polymer adopts a configuration where the hydrocarbon tail is interacting with the octane molecules.

Journal Article↗
PubMed1999

Bicyclo[3.2.1]octanes: synthesis and inhibition of binding at the dopamine and serotonin transporters.

Herein we report the synthesis of a series of bicyclo[3.2.1]octanes and their binding characteristics at the dopamine and serotonin transporters. The data confirm that a heteroatom at position 8 of the tropane nucleus is not a prerequisite for binding since the bicyclo[3.2.1]octanes prove potent inhibitors of both transporters. Therefore the three-dimensional topology of the ligand may be more important than specific functionality with respect to stereospecific binding at the acceptor site.

Bridged Bicyclo Compounds↗
PubMed2000

2-Carbomethoxy-3-aryl-8-bicyclo[3.2.1]octanes: potent non-nitrogen inhibitors of monoamine transporters.

Cocaine is a potent central nervous system stimulant with severe addiction liability. Its reinforcing and stimulant properties derive from inhibition of monoamine transport systems, in particular the dopamine transporter (DAT). This inhibition results in an increase in synaptic dopamine with subsequent stimulation of postsynaptic dopamine receptors. A wide variety of ligands manifest potent inhibition of the DAT, and these ligands include 3-aryltropane as well as 8-oxa-3-aryltropane analogues of cocaine. There has been considerable effort to determine structure-activity relationships of cocaine and congeners, and it is becoming clear that these inhibitors do not all interact with the DAT in the same manner. The functional role of the 8-heteroatom is the focus of this study. We describe the preparation and biology of a series of 2-carbomethoxy-3-arylbicyclo[3.2.1]octane analogues. Results show that methylene substitution of the amine or ether function of the 8-hetero-2-carbomethoxy-3-arylbicyclo[3.2.1]octanes yields potent inhibitors of monoamine transport. Therefore neither nitrogen nor oxygen are prerequisites for binding of tropane-like ligands to monoamine transporters.

Animals↗
PubMed1995

Improving the affinity and selectivity of a nonpeptide series of cholecystokinin-B/gastrin receptor antagonists based on the dibenzobicyclo[2.2.2]octane skeleton.

We have recently described a novel series of nonpeptidic cholecystokinin-B (CCKB)/gastrin receptor antagonists based on a dibenzobicyclo[2.2.2]octane skeleton. We wish now to report on compounds arising out of our earlier work which have substantially greater affinity as antagonists for the CCKB/gastrin receptor system and which maintain, or improve on, the already high selectivity with respect to CCKA receptors. Thus, cis-7-[[[(1S)-[[3,5-dicarboxy-phenyl)amino]carbonyl]-2- phenylethyl]amino]carbonyl]-8-[[(1-adamantylmethyl)amino]- carbonyl]-2,3:5,6-dibenzobicyclo[2.2.2]octane expressed a pKi of 8.80 in mouse cortical membranes at CCKB/gastrin receptors. The selectivity for these receptors over CCKA receptors was in the order of 1000-fold.

Animals↗
PubMed1990

Synthesis and serotonin binding site studies of some conformationally restricted indolylethylamine analogues based on 2-amino-3-(3'-indolyl)bicyclo[2.2.2]octane.

The bicycloannulation reaction between cyclohexenone and indolyl enamines yields trans-3-(cyclic amino)-2-(3'-indolyl)bicyclo[2.2.2]octan-5-ones, and these adducts are conformationally restricted analogues of indolylethylamine (tryptamine) which exhibit structure-dependent affinity for the serotonin 5HT2 and 5HT1a receptors. The stereochemistry of the isomeric endo and exo adducts obtained is assigned from the 1H NMR spectra of the specifically deuterated alkenes prepared from the ketones by the Bamford-Stevens reaction. Molecular mechanics calculations indicate that the conformational flexibility of the amino and indolyl groups is restricted through van der Waals interactions with the bridges of the bicyclic unit. These compounds inhibit the binding of [3H]ketanserin to 5HT2 sites in mouse cerebrocortical membranes, and the binding of [3H]-8-hydroxy-2-(di-n-propylamino)tetralin ([3H]-8-OH-DPAT) to 5HT1a sites in mouse hippocampal membranes. The endo compounds are the most potent, and molecular mechanics calculations indicate that these isomers have a less bulky bicyclo bridge proximate to the amine group and more conformational freedom about the C alpha-C beta-N(+)-H dihedral angle (tau 3). In the 5HT2 assay, endo-trans-3-(N-piperidinyl)-2-(3'-indolyl)bicyclo[2.2.2]octan-5-one (10a) is the most potent, and endo-trans-3-(N-pyrrolidinyl)-2-(3'-indolyl)bicyclo[2.2.2]oct-5-ene (12a) is the most potent in the 5HT1a assay. A phenyl-substituted adduct shows the least affinity in these two assays. These data provide insight into the structural differences between the 5HT1a and 5HT2 receptor sites.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1977

Antifilarial agents. 3-Aminopyrrolidine and 1,4-diazabicyclo[3.2.1]octane derivatives as analogues of diethylcarbamazine.

3-Aminopyrrolidines bearing acyl substituents on either nitrogen and N-acylated 1,4-diazabicyclo[3.2.1]octanes are potent microfilaricides in the Litomosoides carinii gerbil test system but have no effect on adult worms. The high activity of the pyrrolidine derivatives establishes that diethylcarbamazine (DEC) like antifilarial activity does not require that both pharmacophores be incorporated into one ring. Results with the 1,4-diazabicyclo[3.2.1]octanes establish that an axial conformation of the alkyl substituent corresponding to the equatorial N-methyl group of diethylcarbamazine is fully consistent with high activity. Other conformational consideration pertinent to DEC analogues are discussed.

Animals↗
PubMed1976

2-Azabicyclo (2.2.2)octane analogues of the prodine analgetics.

The synthesis and analgetic activity of analogues of prodine-type analgetics in which the conformation of the piperidine ring is restricted in the boat form using the 2-azabicyclo (2.2.2)octane nucleus are reported. One of these analogues, 2-methyl-6-trans-phenyl-6-cis-propionoxy-2-azabicyclo (2.2.2)octane (3), showed significant analgetic activity (ED50 equals 3.1 mg/kg).

Alphaprodine↗
PubMed1976

Trichothecene analogues. 1. 1,5-Dioxaspiro(2.5)octanes.

Seven 1,5-dioxaspiro[2.5]octanes were synthesized and tested in the mouse P388 lymphocytic leukemia screen and the mouse Ehrlich ascites screen. These compounds possess the "epoxypyran" structure which has been believed to be the active portion of the trichothecene class of sesquiterpene tumor inhibitors. Three of the compounds were found to have marginal to moderate activity in the Ehrlich ascites screen (inhibition 74.1-86.3%) and low activity in the P388 screen (T/C = 126-131). A carbocyclic analogue, 1-oxaspiro[2.5]octane (9), was moderately active in both screens (inhibition 78.8%, T/C = 140). In the Ehrlich ascites screen, T-2 toxin (2) was about 25 times more potent than 9. None of the spirooctanes studied caused any skin irritation in 10-mg doses on the skin of rabbits, whereas 2 caused extensive necrosis at 0.1-mg doses.

Animals↗
PubMed1983

Synthesis and transport applications of 3-aminobicyclo[3.2.1] octane-3-carboxylic acids.

The isomeric 3-aminobicyclo[3.2.1]octane-3-carboxylic acids were synthesized and compared with the widely used (1R,2S,4S)-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid as to specificity to the Na+-independent membrane transport system L of the Ehrlich ascites tumor cell and of the rat hepatoma cell line HTC. The presence of an additional methylene group in the ring system leads to an optically symmetrical amino acid, with the advantages that the product is devoid of isomeric contamination. Hence, optical resolution is not necessary to secure a homogeneous test substrate for discrimination of amino acid transport systems. Through its inhibitory action on the cellular uptake of known system-specific amino acids, the bicyclo[3.2.1]octane amino acid proved more reactive than the bicycloheptane analogue with the Na+-independent amino acid transport system of the test cells and not perceptibly reactive with the accompanying Na+-dependent systems. Recent evidence of the presence of a second component of Na+-independent amino acid transport, beyond system L, increases the importance of securing a variety of possibly discriminatory model substrates.

Amino Acids↗
PubMed1998

Mono- and disubstituted-3,8-diazabicyclo[3.2.1]octane derivatives as analgesics structurally related to epibatidine: synthesis, activity, and modeling.

A series of 3,8-diazabicyclo[3.2.1]octanes substituted either at the 3 position (compounds 1) or at the 8 position (compounds 2) by a chlorinated heteroaryl ring were synthesized, as potential analogues of the potent natural analgesic epibatidine. When tested in the hot plate assay, the majority of the compounds showed significant effects, the most interesting being the 3-(6-chloro-3-pyridazinyl)-3,8-diazabicyclo[3.2.1]octane (1a). At a subcutaneous dose of 1 mg/kg, 1a induced a significant increase in the pain threshold, its action lasting for about 45 min. 1a also demonstrated good protection at a dose of 5 mg/kg in the mouse abdominal constriction test, while at 20 mg/kg it completely prevented the constrictions in the animals. Administration of naloxone (1 mg/kg i.p.) did not antagonize its antinociception while mecamylamine (2 mg/kg i.p.) did, thus suggesting the involvement of the nicotinic system in its action. Binding studies confirmed high affinity for the alpha 4 beta 2 nAChR subtype (Ki = 4.1 +/- 0.21 nM). nAChR functional activity studies on three different cell lines showed that 1a was devoid of any activity at the neuromuscular junction. Finally, due to the analogy in their pharmacological profile with that of epibatidine, compounds were compared from a structural and conformational point of view through theoretical calculations and high-field 1H NMR spectroscopy. Results indicate that all of them present one conformation similar to that of epibatidine.

Abdominal Muscles↗
PubMed1999

Synthesis and pharmacology of site-specific cocaine abuse treatment agents: 2-substituted-6-amino-5-phenylbicyclo[2.2.2]octanes.

A series of 2-substituted-6-amino-5-phenylbicyclo[2.2.2]octanes was synthesized and tested for inhibitor potency in [(3)H]WIN 35,428 (WIN) binding at the dopamine (DA) transporter and [(3)H]DA uptake assays. To demonstrate transporter selectivity for the compounds, inhibitor potency was also tested using [(3)H]nisoxetine and [(3)H]paroxetine binding assays for the norepinephrine (NE) and serotonin (5-HT) transporters, respectively. Synthesis was accomplished by bisannulation of the enamine derived from phenylacetaldehyde and dimethylamine with 2-cyclohexenone to give a mixture of endo- and exo-trans-6-amino-5-phenylbicyclo[2.2. 2]octan-2-ones. The separated ketones were reduced to the four diastereomeric alcohols which were converted to acetyl and benzoyl esters. The ketones, alcohols, and acetyl esters generally have low affinity for the three transporters and do not effectively inhibit the uptake of [(3)H]DA. In all cases, the benzoates show significantly greater inhibition of WIN binding compared to the corresponding ketones, alcohols, or acetate esters. One compound, (1R/S,4R/S)-6R/S-(N,N-dimethylamino)-5R/S-phenylbicyclo[2.2. 2]oct-2S/R-yl benzoate, is almost as potent as cocaine in binding to the DA transporter (IC(50) = 270 nM versus 159 nM for cocaine). The C-2 epimer, (1R/S,4R/S)-6R/S-(N, N-dimethylamino)-5R/S-phenylbicyclo[2.2.2]oct-2R/S-yl benzoate, was selective and potent in binding to the 5-HT transporter (IC(50) = 53 nM versus 1050 nM for cocaine) as compared to the DA transporter (IC(50) = 358 nM). A preliminary molecular modeling study of the benzoyl esters indicates that their relative potencies in the WIN binding assay are not correlated to the nitrogen to benzoate phenyl (centroid) distance or to the deviation of the nitrogen from the plane defined by the benzoate ring.

Animals↗
PubMed2002

Substituent effects on the acidity of weak acids. 1. Bicyclo[2.2.2]octane-1-carboxylic acids and bicyclo[1.1.1]pentane-1-carboxylic acids.

The acidities of 3- and 4-substituted bicyclooctane-1-carboxylic acids and 3-substituted bicyclo[1.1.1]pentane-1-carboxylic acids have been calculated at the MP2/6-311++G** theoretical level. There is good agreement between the calculated and observed gas-phase acidities. The acidities of the 4-substituted bicyclooctane acids were found to be linearly dependent on the C-X bond dipoles, as expected from a field effect. The substituents had a negligible effect on the electron density at C1. The difference in acidity between 4-chlorobicyclo[2.2.2]octane-1-carboxylic acid and the parent acid (6.2 kcal/mol) is reproduced by the Kirkwood-Westheimer treatment of substituent effects on acidity, but only if the bicyclooctane ring is given an effective dielectric constant of unity. The acidities of the 3-substituted bicyclooctane acids are linearly related to the corresponding 4-substituted acids with a slope of 0.9. The acidities of the 3-substituted bicyclo[1.1.1]pentane-1-carboxylic acids are linearly related to the C-X bond dipoles for this ring system (which are different than those for the bicyclooctanes), and they are also linearly related to the acidity of the 4-substituted bicyclo[2.2.2]octanecarboxylic acids with a slope of 1.34. The larger slope is due to the smaller bridgehead-bridgehead distance in the bicyclopentane ring than in bicyclo[2.2.2]octane.

Journal Article↗
PubMed2006

Kinetics study of OH radical reactions with n-octane, n-nonane, and n-decane at 240-340 K using the relative rate/discharge flow/mass spectrometry technique.

The kinetics of the reactions of hydroxyl radical with n-octane (k1), n-nonane (k2), and n-decane (k3) at 240-340 K and a total pressure of approximately 1 Torr has been studied using relative rate combined with discharge flow and mass spectrometer (RR/DF/MS) technique. The rate constant for these reactions was found to be positively dependent on temperature, with an Arrhenius expression of k1 = (2.27 +/- 0.21) x 10(-11)exp[(-296 +/- 27)/T], k2 = (4.35 +/- 0.49) x 10(-11)exp[(-411 +/- 32)/T], and k3 = (2.26 +/- 0.28) x 10(-11)exp[(-160 +/- 36)/T] cm3 molecule(-1) s(-1) (uncertainties taken as 2sigma), respectively. Our results are in good agreement with previous studies at and above room temperature using different techniques. Assuming that the reaction of alkane with hydroxyl radical is the predominant form for loss of these alkanes in the troposphere, the atmospheric lifetime for n-octane, n-nonane, and n-decane is estimated to be about 43, 35, and 28 h, respectively.

Journal Article↗
PubMed2002

Simple construction of bicyclo[4.3.0]nonane, bicyclo[3.3.0]octane, and related benzo derivatives by palladium-catalyzed cycloalkenylation.

[reaction: see text] Bicyclo[4.3.0]nonanes (hydrindanes) and bicyclo[3.3.0]octanes (octahydropentalenes) are easily synthesized by palladium-catalyzed cycloalkenylations. Additionally, benzo-fused bicyclo[3.3.0]octanes are prepared for the first time through intramolecular coupling between silyl enol ethers and aromatic rings in the presence of catalytic palladium acetate.

Journal Article↗
PubMed2004

Corrugation energy for octane on Cu(111).

The energy barrier for sliding of octane on Cu(111) is estimated from an experimental datum for the Brillouin-zone-center gap for translation of a monolayer solid of the octane.

Journal Article↗