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At least 253 records · Page 14Linked to original sources
PubMed1982

Rigid analogues of dopamine: synthesis and interaction of 6-exo- and 6-endo-(3',4'-dihydroxyphenyl)-2-azabicyclo[2.2.2]octanes with dopamine uptake sites and receptors.

Two isomeric 6-endo- and 6-exo-(3',4'-dihydroxyphenyl) derivatives (1 and 2) of 2-azabicyclo[2.2.2]octane were synthesized as semirigid analogues of dopamine (DA) to help evaluate the preferred conformation of dopamine at the uptake site of the presynaptic nerve terminal and at the DA receptor. Against the uptake of 0.1 microM [3H]DA by a synaptosomal preparation of corpus striatum from the reserpine-pretreated rat, 2 was found to have a weak inhibitory effect that was three times greater than that of 1 (IC50 = 32 vs. 110 microM). Interactions with DA receptors were assessed with competition for binding of [3H]apomorphine (APO) and on the effect on DA-sensitive adenylate cyclase. Compounds 1 and 2 were both virtually inactive against the binding of 0.5 nM [3H]APO at a screening concentration of 100 microM. The experimental compounds also exhibited only slight adenylate cyclase stimulation in rat striatal homogenates, with 1 appearing to be somewhat more active (at 50 or 400 microM). The weak activities of 1 and 2 and their relatively small differences in activity in these test systems suggest that the DA analogues interact only weakly with the DA transport and receptor sites, possibly as a result of the steric interference caused by the bulky bicyclic ring.

Adenylyl Cyclases↗
PubMed1982

Synthesis of prostanoids with bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, and bicyclo[2.2.2]octane ring systems. Activities of 15-hydroxy epimers on human platelets.

A number of prostanoids with bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, and bicyclo[2.2.2]octane ring systems have been prepared by routes which allow the introduction of the omega chain after the alpha chain. The introduction of a 16-p-halophenoxy substituent confers platelet aggregation activity on both 15 alpha- and 15 beta-hydroxy epimers. In the case of the pinane thromboxane ring system, the natural omega-chain compound is an inhibitor of aggregation, whereas the 16-p-fluorophenoxy analogue is a potent aggregation agent.

Bridged Bicyclo Compounds↗
PubMed1987

6-Methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate (azaprophen), a highly potent antimuscarinic agent.

The synthesis and antimuscarinic properties of 6-methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate (1, azaprophen) are described. Azaprophen is 50 times more potent than atropine as an antimuscarinic agent as measured by the inhibition of acetylcholine-induced contraction of guinea pig ileum and is more than 1000 times better than atropine in its ability to block alpha-amylase release from pancreatic acini cells induced by carbachol. In addition, azaprophen is 27 times more potent than atropine as an inhibitor of binding of [N-methyl-3H]scopolamine to muscarinic receptors, with human IMR-30 neuroblastoma cells. The potencies of azaprophen and atropine in altering operant behavior were similar. The structural features of 1 are compared to the standard anticholinergic drugs atropine and quinuclidinyl benzilate by using energy calculations and molecular modelling studies. A modification of the pharmacophore model hypothesis for cholinergic agents is suggested.

Acetylcholine↗
PubMed2001

Synthesis of 6- and 7- hydroxy-8-azabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters.

Cocaine is a potent stimulant of the central nervous system. Its reinforcing and stimulant effects are related to its ability to inhibit the membrane bound dopamine transporter (DAT). Inhibition of the DAT causes an increase of dopamine in the synapse with a resultant activation of postsynaptic receptors. The rapid onset and short duration of action of cocaine contribute to its high addictive potential. Consequently, the design of tropane analogues of cocaine that display longer onset times on the DAT and extended duration of action is driven by the need to develop cocaine medication. This study extends the exploration of bridge hydroxylated azabicyclo[3.2.1]octanes (tropanes). A series of 6- and 7-hydroxylated tropanes was prepared and evaluated biologically. Structure activity relationships lead to the following conclusions. Bridge hydroxylated tropanes retain biological enantioselectivity but display higher DAT versus SERT selectivity, particularly for the 3 alpha-aryl compounds as compared with the 3beta-aryl compounds, than the bridge unsubstituted analogues. The 7-hydroxyl compounds are more potent at the DAT than their 6-hydroxyl counterparts. The general SAR of the tropanes is maintained and the rank order of potencies based on substitution at the C3 position remains 3,4-dichloro > 2-naphthyl > 4-fluoro > phenyl.

Animals↗
PubMed2005

Discovery of the alpha7 nicotinic acetylcholine receptor agonists. (R)-3'-(5-Chlorothiophen-2-yl)spiro-1-azabicyclo[2.2.2]octane-3,5'-[1',3']oxazolidin-2'-one as a novel, potent, selective, and orally bioavailable ligand.

Recent advances in molecular biology suggest that neuronal nicotinic acetylcholine receptors play important roles in the central nervous system (CNS). Of these receptors, the alpha7 group has recently attracted interest for its CNS-related actions and is looked to as a potential new class of pharmacological targets for cognition, schizophrenia, sensory gating, and anxiety. In the course of a research program aimed at the discovery of alpha7 receptor agonists with high affinity, subtype selectivity, and good pharmacokinetic profile, we discovered (R)-3'-(5-chlorothiophen-2-yl)spiro-1-azabicyclo[2.2.2]octane-3,5'-[1',3']oxazolidin-2'-one (25). Compound 25 has potent binding affinity (K(i) = 9 nmol/L) and good selectivity toward the other nicotinic subtypes (alpha4beta2 and alpha1beta2gammadelta) and has been found in pharmacokinetic evaluation to have good oral bioavailability and brain permeability.

Administration, Oral↗
PubMed2006

Rational design and enantioselective synthesis of (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid - a novel inhibitor at human glutamate transporter subtypes 1, 2, and 3.

The natural product kainic acid is used as template for the rational design of a novel conformationally restricted (S)-glutamic acid (Glu) analogue, (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid (1a). The target structure 1a was synthesized from commercially available (S)-pyroglutaminol, in an enantioselective fashion, in 14 steps. Pharmacological characterization of 1a at human glutamate transporter subtypes 1, 2, and 3 yielded K(i) values of 127, 52, and 46 microM, respectively. Furthermore, binding studies at native ionotropic Glu (iGlu) receptors revealed low affinity for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-preferring iGlu receptors (IC(50) > 100 microM), whereas affinities for the KAIN-preferring iGlu receptors and the N-methyl-d-aspartate (NMDA)-preferring group of iGlu receptors were in the low micromolar range (IC(50) = 14 and 2.9 microM, respectively). At metabotropic Glu receptors (mGluR), EC(50) values for 1a were >1000 microM for mGluR1 and 4, representing group I and III, respectively, and approximately 1000 microM (agonist) for mGluR2, representing group II.

Animals↗
PubMed2006

(R)-3'-(3-methylbenzo[b]thiophen-5-yl)spiro[1-azabicyclo[2,2,2]octane-3,5'-oxazolidin]-2'-one, a novel and potent alpha7 nicotinic acetylcholine receptor partial agonist displays cognitive enhancing properties.

Recent studies have suggested that the alpha7 nicotinic acetylcholine receptors play important roles in learning and memory. Herein, we describe our research of the structure-activity relationships (SAR) in a series of (S)-spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin]-2'-ones bearing various bicyclic moieties to discover novel alpha7 receptor agonists. Through a number of SAR studies on the series, we have found out that inhibition of CYP 2D6 isozyme, which was a primary obstacle for the previously identified compound, was avoidable by the introduction of bicyclic moieties. Chemical optimization of the series led to the identification of a novel and potent alpha7 nicotinic acetylcholine receptor partial agonist 23. This compound not only possessed high binding affinity (K(i) = 3 nmol/L) toward the alpha7 receptor but also showed agonistic activity even at a concentration of 0.1 micromol/L. In addition, compound 23 improved cognition in several rat models, which might suggest the potential of the alpha7 receptor partial agonist for the treatment of neurological disorders including cognitive dysfunction.

Animals↗
PubMed1996

Synthesis of 3 beta-aryl-8-azabicyclo[3.2.1]octanes with high binding affinities and selectivities for the serotonin transporter site.

A novel entry to tropane analogs of cocaine was developed based on the reaction of rhodium-stabilized vinylcarbenoids with pyrroles. These analogs were tested in binding to dopamine, serotonin (5-HT), and norepinephrine transporters in membranes from rat striatum and frontal cortex. In all the analogs, the aryl group at the 3 position was directly bound to the tropane ring and an ethyl ketone moiety was present at the 2 position. By appropriate modification of the aryl and nitrogen substituents, highly potent and 5-HT selective tropanes were prepared. The most potent and selective compound was 3 beta-[4-(1-methylethenyl)phenyl]-2 beta-propanoyl-8-azabicyclo[3.2.1]octane (13b) which had a Ki of 0.1 nM at 5-HT transporters and was 150 times more potent at 5-HT vs dopamine transporters and almost 1000 times more potent at 5-HT vs norepinephrine transporters.

Animals↗
PubMed1997

Dual inhibition of human leukocyte elastase and lipid peroxidation: in vitro and in vivo activities of azabicyclo[2.2.2]octane and perhydroindole derivatives.

A series of potent and selective human leukocyte elastase (HLE) inhibitors of the Val-Pro-Val type has been developed. Initially, the central proline residue was replaced by nonnatural amino acids Phi ((2S,3aS,7aS)-perhydroindole-2-carboxylic acid) and Abo ((3S)-2-azabicyclo-[2.2.2]octane-3-carboxylic acid), and secondly several groups able to confer antioxidant properties to the molecule were introduced at the lipophilic N-terminal side chain. When compared to reference inhibitors, in vitro HLE inhibitory potency was maintained (10-100 nM) both with compounds containing the antioxidant moiety at the end of the N-terminal side chain and with compounds in which the N-terminal valine of the tripeptidic sequence had been replaced by a epsilon-substituted lysine. The lipidic peroxidation inhibitory potency of this series of inhibitors was found to be similar to that of the reference antioxidant compounds (around 1 microM). Moreover, HLE-induced hemorrhage in the hamster lung was effectively prevented (40-60% at 15 micrograms/kg) by most of the inhibitors tested when administered intratracheally 3 h before instillation of elastase. Among the most active analogs, compounds 11a,c,g were still active when administered 18 h before elastase. Interestingly, compound 14a was able to prevent HLE-mediated lung damage when administered 72 h prior to enzymatic challenge, indicating exceptional stability and retention in the lung. Finally, in a 14-day chronic model of emphysema in the hamster, 14a significantly conserved alveolar spaces, a marker of lung tissue destruction, and was more potent than reference inhibitor ICI 200 880. This indicates that addition of peroxidation inhibitory properties to an HLE inhibitor can provide a powerful in vivo inhibitor of pulmonary tissue destruction.

Animals↗
PubMed2000

Synthesis, molecular modeling, and opioid receptor affinity of 9, 10-diazatricyclo[4.2.1.1(2,5)]decanes and 2,7-diazatricyclo[4.4.0. 0(3,8)]decanes structurally related to 3,8-diazabicyclo[3.2. 1]octanes.

Various lines of evidence, including molecular modeling studies, imply that the endoethylenic bridge of 3,8-diazabicyclo[3.2. 1]octanes (DBO, 1) plays an essential role in modulating affinity toward mu opioid receptors. This hypothesis, together with the remarkable analgesic properties observed for N(3) propionyl, N(8) arylpropenyl derivatives (2) and of the reverted isomers (3), has prompted us to insert an additional endoethylenic bridge on the piperazine moiety in order to identify derivatives with increased potency toward this receptor class. In the present report, we describe the synthesis of the novel compounds 9,10-diazatricyclo[4.2. 1.1(2,5)]decane (4) and 2,7-diazatricyclo[4.4.0.0(3,8)]decane (5), as well as the representative derivatives functionalized at the two nitrogen atoms by propionyl and arylpropenyl groups (6a-e, 7a-d). Opioid receptor binding assays revealed that, among the compounds tested, the N-propionyl-N-cinnamyl derivatives 6a and 7a exhibited the highest mu-receptor affinity, and remarkably, compound 7a displayed in vivo (mice) an analgesic potency 6-fold that of morphine.

Analgesics↗
PubMed2001

Novel bicyclic nucleoside analogue (1S,5S,6S)-6- hydroxy-5-hydroxymethyl-1-(uracil-1-yl)-3,8-dioxabicyclo[3.2.1]octane: synthesis and incorporation into oligodeoxynucleotides.

The novel bicyclic nucleoside (1S,5S,6S)-6-hydroxy-5-hydroxymethyl-1-(uracil-1-yl)-3,8-dioxabicyclo[3.2.1]octane [2'-deoxy-1'-C,4'-C-(2-oxapropano)uridine] (15), expected to be restricted into an O4'-endo furanose conformation, was synthesized from the known 1-(3'-deoxy-beta-D-psicofuranosyl)uracil 5. The phosphoramidite derivative of 15 was successfully incorporated into oligodeoxynucleotides using standard methods, and thermal denaturation studies showed moderate decreases in duplex stabilities of -2.1 and -1.5 degrees C per modification toward complementary DNA and RNA, respectively.

Bridged Bicyclo Compounds↗
PubMed2002

Development of new chiral building blocks for synthesis of bicyclo[3.3.0]octane compounds.

Ti(II)-mediated tandem cyclization of (E)-5-(tert-butyldimethylsilyloxy)-8-trimethylsilyl-2-octen-7-ynoate (7) prepared from commercially available optically active epichlorohydrin (2) proceeded diastereoselectively to provide 7-(tert-butyldimethylsilyloxy)-2-trimethylsilylbicyclo[3.3.0]oct-1-en-3-one (1), which serves as a useful chiral building block or intermediate to prepare a variety of compounds having a bicyclo[3.3.0]octane framework.

Journal Article↗
PubMed2002

Intramolecular hydrogen abstraction reaction promoted by alkoxy radicals in carbohydrates. Synthesis of chiral 2,7-dioxabicyclo[2.2.1]heptane and 6,8-dioxabicyclo[3.2.1]octane ring systems.

The reaction of specifically protected anhydroalditols with (diacetoxyiodo)benzene or iodosylbenzene and iodine is a mild and selective procedure for the synthesis of chiral 6,8-dioxabicyclo[3.2.1]octane and 2,7-dioxabicyclo[2.2.1]heptane ring systems under neutral conditions. This reaction can be considered to be an intramolecular glycosidation that goes through an intramolecular hydrogen abstraction promoted by an alkoxy radical followed by oxidation of the transient C-radical intermediate to an oxycarbenium ion. This methodology is useful not only for the preparation of chiral synthons but also for the selective oxidation of specific carbons of the carbohydrate skeleton, constituting a good procedure for the synthesis of protected uloses.

Bridged Bicyclo Compounds, Heterocyclic↗
PubMed2004

Enantioselective acylation using a second-generation P-aryl-2-phosphabicyclo[3.3.0]octane catalyst.

The synthesis of P-aryl-2-phosphabicylco[3.3.0]octane x HBF4 salts 3a and 3c is described. Incorporation of the P-3,5-di-tert-butyl-4-methoxyphenyl group in 3c allows use of a less expensive aryl bromide starting material. Deprotonation of the air-stable salts in situ with triethylamine releases the corresponding phosphines 1a and 1c for use in the kinetic resolution of representative secondary alcohols. The method is convenient for small-scale experiments and affords enantioselectivities s close to the values obtained using the free phosphines 1a and 1b in cases where s is ca. 40 or lower.

Journal Article↗
PubMed2004

A chiral synthesis of (-)-spiro[1-azabicyclo[2.2.2]octane-3,5'- oxazolidin-2'-one]: a conformationally restricted analogue of acetylcholine that is a potent and selective alpha7 nicotinic receptor agonist.

A direct, short chiral synthesis of the selective alpha7 nicotinic receptor agonist (-)-spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin-2'-one] (AR-R17779) is presented. The key step utilized attack of the dianion of the (R)-HYTRA ester [(R)-(+)-2-hydroxy-1,2,2-triphenylethyl acetate] on quinuclidin-3-one, followed by a selective precipitation of the diasteriomeric tertiary alcohol that led to (S)-(-)-AR-R17779 in two additional steps.

Bridged-Ring Compounds↗
PubMed2004

Probing the formation of bicyclo[4.2.0]octan-1-ols.

Reaction of lithium enolates of simple ketones with (+/-)-phenyl vinyl sulfoxide has potential for the convergent construction of complex fused ring systems containing a bicyclo[n.2.0]alkan-1-ol. The formation of sulfinylbicyclo[4.2.0]octan-1-ols 1-3 from the lithium enolate of cyclohexanone with (+/-)-phenyl vinyl sulfoxide or (R)-(+)-p-tolyl vinyl sulfoxide 18 was used to probe the mode of this novel cyclization reaction. Using phenyl vinyl sulfoxide, variations in the reaction lighting and solvent were investigated, in conjunction with radical trapping (TEMPO) and isotope labeling (deuterium) experiments. Cyclization to form sulfinylbicyclooctanols 1-3 is likely to proceed via an intermediate that ring closes to the bicycloalkanol anion 11 and was presently favored by the use of solvents such as THF or DME.

Journal Article↗