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At least 19 recordsLinked to original sources
PubMed1995

3-Heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives as muscarinic antagonists. Synthesis and structure-activity relationships.

A number of 3-heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives have been prepared and evaluated for muscarinic and antimuscarinic properties. The affinities of the new compounds (13, 14, 16-32, and 36-52a,b) were tested in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate [(-)-[3H]QNB] as the radioligand and in a functional assay using isolated guinea pig urinary bladder. The present compounds behaved as competitive muscarinic antagonists in the urinary bladder. The highest receptor binding affinity, Ki (cortex) = 9.6 nM, was observed for 3-(2-benzofuranyl)quinuclidin-2-ene (31). The corresponding 3-benzofuranyl (36) and 3-benzothienyl (37) homologues had about 3.5-fold lower affinity for cortical muscarinic receptors. All quinuclidin-3-ol derivatives (14 and 16-25) had lower binding affinities for the different muscarinic receptor subtypes than the corresponding quinuclidin-2-ene analogues when examined in the various tissue homogenates. In general, the new compounds showed low subtype selectivity. The structure-affinity relationships are discussed in terms of differences in proton basicity of the azabicyclic nitrogen and differences in geometric, conformational, and/or electronic properties of the compounds. The cortical antimuscarinic potency is also related to the complementarity of the compounds to the putative binding site of the muscarinic m1 receptor.

Animals↗
PubMed2003

Correlation between pK(a) and reactivity of quinuclidine-based catalysts in the Baylis-Hillman reaction: discovery of quinuclidine as optimum catalyst leading to substantial enhancement of scope.

The reactivity of a variety of quinuclidine-based catalysts in the Baylis-Hillman reaction has been examined, and a straightforward correlation between the basicity of the base and reactivity has been established, without exception. The following order of reactivity was established with pK(a)'s of the conjugate acids (measured in water) given in parentheses: quinuclidine (11.3), 3-hydroxyquinuclidine (9.9), DABCO (8.7), 3-acetoxyquinuclidine (9.3), 3-chloroquinuclidine (8.9), and quinuclidinone (7.2). The higher than expected reactivity of DABCO, based on its pK(a), was analyzed by comparing the relative basicity of DABCO and 3-acetoxyquinuclidine in DMSO. It was found that in aprotic solvent, DABCO was 0.6 pK(a) units more basic than 3-acetoxyquinuclidine, thus establishing a direct link between pK(a) of the amine and its reactivity. In contrast to previous literature work that reported the contrary, quinuclidine, which has the highest pK(a), was found to be the most active catalyst. The reaction profile with quinuclidine showed significant autocatalysis, which suggested that the presence of proton donors might further enhance rates. Thus, a series of additives bearing polar X-H bonds were investigated and it was found that methanol, triethanolamine, formamide, and water all provided additional acceleration. Methanol was found to be optimum, and the powerful combination of quinuclidine with methanol was tested with a host of aldehydes and Michael acceptors. Not only were the reactions more efficient and faster than previously reported, but now new substrates that were previously unreactive could be employed. Notable examples include the use of acetylenic aldehydes and the employment of vinyl sulfones, acrylamides, delta-lactones, and even alpha,beta-unsaturated esters bearing a beta-substituent.

Journal Article↗
PubMed1999

Kinetics and Mechanism of the Reactions of Quinuclidines with Ethyl S-Aryl Thiolcarbonates.

The reactions of quinuclidines with ethyl S-(4-nitrophenyl) thiolcarbonate (NPTC), ethyl S-(2,4-dinitrophenyl) thiolcarbonate (DNPTC), and ethyl S-(2,4,6-trinitrophenyl) thiolcarbonate (TNPTC) are subjected to a kinetic study in aqueous solution, 25.0 degrees C, ionic strength 0.2 (KCl). The reactions are studied by following spectrophotometrically (400 nm) the release of the corresponding substituted benzenethiolate anion. Under quinuclidine excess, pseudo-first-order rate coefficients (k(obsd)) are found. Plots of k(obsd) vs [N] (N is the free substituted quinuclidine) are linear and pH independent, with slope k(N). The Brönsted-type plots (log k(N) vs pK(a) of quinuclidinium ions) are linear, with slope beta = 0.85 for NPTC, in agreement with a stepwise mechanism where the breakdown of a tetrahedral addition intermediate (T(+/-)) is rate determining, and beta = 0.54 and 0.47 for DNPTC and TNPTC, respectively, consistent with a concerted mechanism. By comparison of the reactions under investigation among them and with similar aminolyses, the following conclusions can be drawn: (i) Substitution of the 4-nitrobenzenethio group in T(+/-) by 2,4-dinitrobenzenethio or 2,4,6-trinitrobenzenethio destabilizes the tetrahedral intermediate. (ii) Quinuclidines destabilize the tetrahedral intermediate relative to secondary alicyclic amines, anilines, and pyridines. The leaving abilities of isobasic amines from T(+/-) follow the sequence pyridines < anilines < secondary alicyclic amines < quinuclidines. (iii) Quinuclidines are more reactive toward the carbonyl group of phenyl 4-nitrophenyl carbonate than that of NPTC.

Journal Article↗
PubMed1987

Synthesis and cardiac electrophysiological activity of 2- and 3-[(substituted phenyl)alkyl]quinuclidines. Structure-activity relationships.

The syntheses and cardiac electrophysiological effects of 21 2- and 3-substituted quinuclidines and some quaternary ammonium derivatives are described. The 2-substituted quinuclidines 2-8 were prepared by alkylation of 2-methylene-3-quinuclidinone. The Wittig reaction with 3-quinuclidinone afforded the 3-substituted derivative 9, which was subsequently converted to 10 and 11. The electrophysiological profiles of the compounds were determined in canine cardiac Purkinje fibers and ventricular muscle strips. The 3-[(substituted phenyl)alkyl]quinuclidines selectively increased action potential duration (Vaughan Williams class III activity). In the 2-substituted series some of the compounds both increased action potential duration and decreased conduction velocity (class I activity). For some of the 2-substituted quinuclidines, appropriate substitution of the phenyl ring was shown to be a requirement for significant class III electrophysiological activity. Selected compounds were efficacious in a programmed electrical stimulation model in the anesthetized dog.

Action Potentials↗
PubMed2005

Synthesis and antimuscarinic properties of quinuclidin-3-yl 1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives as novel muscarinic receptor antagonists.

In the course of continuing efforts to develop potent and bladder-selective muscarinic M3 receptor antagonists, quinuclidin-3-yl 1-aryl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives and related compounds were designed as conformationally restricted analogues of quinuclidin-3-yl benzhydrylcarbamate (8). Binding assays with rat muscarinic receptor subtypes revealed that the quinuclidin-3-yl 1-aryl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives showed high affinities for the M3 receptor, and selectivity for the M3 receptor over the M2 receptor. Of these derivatives, (+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monohydrochloride (9b) exhibited almost the same inhibitory activity against bladder contraction to that of oxybutynin (1), and more than 10-fold selectivity for bladder contraction versus salivary secretion, demonstrating that 9b may be useful for the treatment of symptoms associated with overactive bladder without having side effects such as dry mouth.

Animals↗
PubMed1999

Quinuclidine inhibitors of 2,3-oxidosqualene cyclase-lanosterol synthase: optimization from lipid profiles.

Novel 3-substituted quinuclidine inhibitors of cholesterol biosynthesis are reported. Compounds were optimized against oxidosqualene cyclase-lanosterol synthase (OSC) inhibition in vivo, rather than by the conventional optimization of structure-activity relationship information based on in vitro OSC inhibition. Thus, examination of HPLC lipid profiles from orally dosed rats showed cholesterol biosynthetic intermediates and whether cholesterol levels were reduced. A new substituted quinuclidine pharmacophore 18a-c was rapidly found for the inhibition of OSC, and the most promising inhibitors were validated by the confirmation of potent OSC inhibition. Compound 16 gave an IC50 value of 83 +/- 11 nM for human and an IC50 value of 124 +/- 14 nM, for rat, coupled with oral and selective inhibition of cholesterol biosynthesis derived from OSC inhibition (rat, ED50 = 1.3 +/- 0.7 mg/kg, n = 5; marmoset, 15 mg/kg dose, n = 3, caused complete inhibition). These 3-substituted quinuclidines, which were derived from a quinuclidine series previously known to inhibit cholesterol biosynthesis at the squalene synthase step, may afford a novel series of hypocholesterolemic agents acting by the inhibition of OSC.

Administration, Oral↗
PubMed2006

A diastereoselective radical cyclization approach to substituted quinuclidines.

A new, concise, and flexible approach to novel quinuclidines has been developed, which employs a phosphorus hydride mediated radical addition/cyclization reaction in the key step. 1,7-Diene 5 reacts with diethyl thiophosphite in an efficient and diastereoselective radical addition/cyclization reaction to give trisubstituted piperidines 4ab. Piperidines 4ab are subsequently converted into 2,5-disubstituted quinuclidines using S(N)2-type cyclizations. Finally, the resulting quinuclidines are shown to undergo novel Horner-Wadsworth-Emmons-type (HWE-type) reactions to give unsaturated quinuclidines 21a and 21b, which have structures similar to that of (-)-quinine 1.

Cyclization↗
PubMed2006

Antiproliferative activities of two novel quinuclidine inhibitors against Toxoplasma gondii tachyzoites in vitro.

OBJECTIVES: To study the antiproliferative effects of ER119884 and E5700, two quinuclidine-based inhibitors of squalene synthase (SQS), against Toxoplasma gondii tachyzoites in epithelial cells. METHODS: The antiproliferative effects of the quinuclidine derivatives, alone or in combination with epiminolanosterol or antifolates, were analysed, resulting in the construction of isobolograms. The ultrastructure of treated tachyzoites was analysed by transmission electron microscopy. RESULTS: The quinuclidine derivatives demonstrated selective anti-T. gondii activity, arresting parasite growth with IC50 values of 0.66 and 0.23 microM for ER119884 and E5700, respectively, after 24 h of interaction and 0.44 and 0.19 microM after 48 h of interaction. Both compounds induced remarkable alterations in the parasite ultrastructure, such as mitochondrial swelling and the presence of autophagosome-like structures, after 24 h of treatment. Combination of these quinuclidine derivatives with the antifolates sulfadiazine and pyrimethamine produced a synergic effect. When epiminolanosterol was combined with E5700, the effect observed was synergic, whereas the combination with ER119884 produced no interaction. CONCLUSIONS: E5700 and ER119884 demonstrated selective activity against T. gondii tachyzoites and are a possible alternative to be used in association with the current therapy. The ultrastructural alterations observed suggest a possible interference with lipid metabolism.

Animals↗
PubMed2004

Crystal and molecular structures of new enantiopure quinuclidines.

X-ray crystal structure analysis was performed on single crystals of two diastereomeric enantiopure quinuclidines, (3R,8R)-3-vinyl-8-hydroxymethyl-quinuclidine (quincoridine, QCD) and (3R,8S)-3-vinyl-8-hydroxymethyl-quinuclidine (quincorine, QCI) as their salts with tartaric and p-toluenesulphonate anions, respectively. The molecules of these quinuclidine derivatives are considered here as fragments of the Cinchona alkaloids, quinidine and quinine. A comparison of the conformational features of QCD, QCI, and Cinchona alkaloids in the crystalline state shows that the molecular geometry of the title compounds is similar to that of threo-alkaloids (e.g., R,R isomer of epicinchonine) rather than to quinidine and quinine. The packing of the molecules in both structures is dominated by intermolecular hydrogen bonds.

Journal Article↗
PubMed2003

Syntheses and biological evaluation of novel quinuclidine derivatives as squalene synthase inhibitors.

Squalene synthase (E.C. 2.5.1.21) catalyses the reductive dimerization of two molecules of farnesyl diphosphate to form squalene and is involved in the first committed step in cholesterol biosynthesis. Inhibition of this enzyme is therefore an attractive target for hypocholesterolemic strategies. A series of quinuclidine derivatives incorporating a tricyclic system was synthesized and evaluated for their ability to inhibit squalene synthase in vitro. A 9H-fluorene moiety was found to be optimal as the tricyclic system for potent inhibitory activity. Improved activity can be achieved with a conformationally constrained three-atom linkage connecting the tricyclic system with the quinuclidine nucleus. Among these compounds, (Z)-3-[2-(9H-fluoren-2-yloxy)ethylidene]-quinuclidine hydrochloride 31 was found to be a potent inhibitor of squalene synthase derived from hamster liver and human hepatoma cells with IC(50) values of 76 and 48 nM, respectively. Oral dosing of compound 31 demonstrated effective reduction of plasma non-HDL cholesterol levels in hamsters.

Animals↗
PubMed1993

2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and isoquinolin-1-ones. Potent conformationally restricted 5-HT3 receptor antagonists.

Several series of N-(quinuclidin-3-yl)aryl and heteroaryl-fused pyridones were synthesized and evaluated for 5-HT3 receptor affinity. In the heteroaryl series, 2-(quinuclidin-3-yl)tetrahydropyrido-[4,3-b]indol-1-one (8a) and the 4,5-alkano-bridged analogues (14 and 15) displayed high 5-HT3 receptor affinity with pKi values > 9. The (3S)-quinuclidinyl isomers had > 10 fold higher affinity than the (3R)-isomers. In a series of 2-quinuclidin-3-yl)isoquinolin-1-ones, derivatives substituted with small lipophilic groups (25b-e) and with 4,5-alkano-bridges (34-36) also displayed high affinity. In particular, the hexahydro-1H-benz[de]isoquinolinone (S,S)-37 was the highest affinity 5-HT3 receptor ligand prepared (pKi 10.4). A number of the high affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the B-J reflex in the anesthetized rat. Again, (S,S)-37 was the most active agent tested (ID50 0.02 microgram/kg i.v.), and this compound was also potent in blocking cisplatin-induced emesis in both the ferret and the dog. Computer modeling studies were performed, and previously reported 5-HT3 receptor antagonist pharmacophore models were refined to include a key lipophilic binding domain.

Animals↗
PubMed2005

Controlled decomposition of an indium trihydride adduct: synthesis and characterization of the first mixed-oxidation-state indium sub-halide complex anion, [In5Br8(quinuclidine)4]-.

The first example of a compound containing a mixed-oxidation-state indium sub-halide complex anion, [In5Br8(quinuclidine)4]-, has been accessed by the controlled decomposition of an indium trihydride adduct, [InH3(quinuclidine)], in the presence of LiBr. An intermediate in this reaction, [InH2Br(quinuclidine)2], has been isolated and suggests that its mechanism involves hydride-bromide exchange, reductive dehydrogenation, and disproportionation processes.

Journal Article↗
PubMed2005

Structure and reactivity of trans-bis[2-(2-chloroethyl)pyridine]palladium chloride (1). A study on the elimination reaction of 1 and 2-(2-chloroethyl)pyridine induced by quinuclidine in acetonitrile.

[reaction: see text] The trans-bis[2-(2-chloroethyl)pyridine]palladium chloride (1) has been prepared and structurally characterized by X-ray spectroscopy and computational study. The X-ray structure of 1 is consistent with the trans isomer (with respect to Pd). The NMR spectrum and the computational study are in agreement with an equilibrium in CD3CN solution between two isomers of the trans structure. The reaction of the palladium complex with quinuclidine in CH3CN, at 25 degrees C, leads to competing elimination and displacement reactions with formation of vinylpyridine and chloroethylpyridine in a ratio of 1.5:1. However, the rate constant for formation of uncoordinated (vinyl)pyridine monitored by HPLC (kQ(HPLC) = 2.3 x 10(-3) M(-1) s(-1)) is nearly 3 times slower than a rate constant monitored spectrophotometrically (kQ = 6.5 x 10(-3) M(-1) s(-1)). This suggests that the initial product of elimination is a palladium complex of vinylpyridine and that displacement from this complex is partially rate determining in the formation of the uncoordinated product. A study by UV spectroscopy at lambda = 295 nm of trans-bis[2-(2-chloroethyl)pyridine-d2]palladium chloride with quinuclidine (Q) has shown the presence of a significant primary kinetic isotope effect, kQ(H)/kQ(D) = 1.8, for the elimination reaction within the Pd complex, 1. The second-order rate constant for the beta-elimination reaction from 2-(2-chloroethyl)pyridine induced by quinuclidine in CH3CN at 25 degrees C is kQ(FREE) = 6.2 x 10(-6) M(-1) s(-1). It can be observed as a significant activation (about 3 orders of magnitude) of the beta-elimination reaction within the complex 1 with respect to the free 2-(2-chloroethyl)pyridine. The possible mechanism in agreement with these results is discussed.

Journal Article↗
PubMed1998

Stereoisomers of 3-(2,3-dihydrobenzofuran-2-yl)quinuclidine: preparation and muscarinic receptor affinities.

The four stereoisomers of the antimuscarinic 3-(2,3-dihydrobenzofuran-2-yl)quinuclidine have been prepared by a method involving chromatographic separation of the racemic diastereoisomers as borane complexes. The relative and absolute configurations of the stereoisomers were determined by X-ray crystallographic methods. The crystal structure of (2'R,3R)-3-(2,3-dihydrobenzofuran-2-yl)quinuclidine.HCl.H2O contains two independent molecules with different conformations of both the quinuclidine moiety and the dihydrofuran ring.

Animals↗
PubMed2002

Photoelectron spectra and electronic structure of some diastereomeric quinuclidine derivatives.

The molecular and electronic structure of three pairs of diastereomeric quinuclidine derivatives (1-6) have been investigated by quantum chemical calculations and UV photoelectron (PE) spectroscopy. Compounds 1-6 each possess a hydroxymethyl group at C2 and an ethyl (1, 2), vinyl (3, 4) or ethynyl group (5, 6) at C5. The diastereomeric pairs differ only in the configuration of carbon C2 to which the hydroxymethyl group is attached. The 1-azabicyclo[2.2.2]octane cages of 1-6 are slightly twisted. The torsion angles show opposite signs in the pseudoenantiomeric pairs and vary only little with the degree of unsaturation in the C5 substituent. In all compounds the hydroxymethyl group forms an intramolecular hydrogen bond with the nitrogen atom of the bicycle in the gas phase (in contrast to the crystalline and liquid state). The PE spectra of the diastereomers are nearly identical. Compared to unsubstituted quinuclidine, the orbital of the nitrogen lone pair electrons n(N) is stabilized by 0.3-0.4 eV, which is a result of partially compensating contributions of the OH...N hydrogen bond and substituent effects. Among these a substantial through-bond interaction of the n(N) with a pi(CC) orbital is detected for 3-6. The marked differences of the properties of 1-6 in the gas phase versus solid state and solution are emphasised. In solution the ethynyl azabicyclics 5 and 6 are more polar than the vinyl analogues 3 and 4.

Cinchona Alkaloids↗
PubMed1996

Inhibition of squalene synthase of rat liver by novel 3' substituted quinuclidines.

Squalene synthase (SQS) is a key enzyme in the biosynthetic pathway for cholesterol and is a target for improved agents to lower plasma levels of low-density lipoprotein (LDL). A series of novel 3' substituted quinuclidines have been discovered as inhibitors of the rat liver microsomal enzyme. In this study, we demonstrate the inhibitory effects in vitro and in vivo, of two examples of the series. When microsomes were preincubated with compounds, before addition of substrate, both 3-(biphenyl-4-yl)quinuclidine (BPQ) and 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (BPQ-OH) were found to cause biphasic inhibition of the enzyme with apparent inhibition constants (K'i) for the sensitive phases of 12 nM and 15 nM, respectively. The K'i values for the insensitive phases were 1.8 microM and 2.9 microM, respectively. The two examples inhibited equally both steps of the SQS-catalysed reaction, as shown by parallel inhibition of 3H+ release and labelled squalene formation from [1-3H]farnesyl pyrophosphate (FPP). BPQ and BPQ-OH were shown to be inhibitors of hepatic sterol synthesis from mevalonate with ED50 values of 10.6 and 7.1 mg/kg, respectively, after acute oral administration to the rat. BPQ-OH was chosen for further study and, to determine its selectivity of effect on the mevalonate pathway in vivo, the effect of a dose of 70 mg/kg on the pattern of labelled mevalonate incorporation into the various lipid fractions of the rat liver was examined. As expected, the incorporation into squalene and sterol products was inhibited by about 70%. An appearance of label in fractions corresponding to farnesyl and geranylgeranylpyrophosphates, as well as the corresponding alcohols, was observed in treated but not control animals. In addition, the administration of compound resulted in the appearance of peaks of mevalonate-derived radioactivity in an acidic fraction believed to represent metabolites of farnesol. Such results are consistent with inhibition of the mevalonate pathway at, and not before, SQS. In contrast, there was a significant increase in the incorporation of labelled mevalonate into ubiquinone 10, and the synthesis of dolichols was apparently unchanged. The results suggest a specific effect of BPQ-OH on rat liver SQS. The compound is, therefore, an interesting lead for further investigation of this class of compounds.

Animals↗
PubMed1995

Quinuclidin-2-ene-based muscarinic antagonists.

A series of achiral 3-heteroaryl substituted quinuclidin-2-ene derivatives and related compounds have been synthesized by facile methods. The compounds were evaluated for muscarinic and antimuscarinic properties in receptor binding studies using (-)-[3H]-QNB as the radioligand and in a functional assay using isolated guinea pig urinary bladder. 3-(2-Benzofuranyl)-quinuclidin-2-ene (15) displayed the highest M1-receptor affinity in the present series (Ki = 9.6 nM).

Animals↗
PubMed2005

Ionic liquid-immobilized quinuclidine-catalyzed Morita-Baylis-Hillman reactions.

[reaction: see text] The ionic liquid-bound quinuclidine catalyzed Baylis-Hillman reactions were investigated. The IL-supported catalyst showed equally good catalytic activity as compared with its nonimmobilized counterpart. The corresponding Baylis-Hillman adducts were obtained in moderate to high yields in all the cases tested. The IL-supported quinuclidine can be readily recovered and reused six times without significant loss of catalytic activity.

Aldehydes↗