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BRIDGED, BICYCLIC HETEROCYCLIC OR SPIRO BICYCLIC HETEROCYCLIC DERIVATIVES OF PYRAZOLO[1,5-A]PYRIMIDINES, METHODS FOR PREPARATION AND USES THEREOF

Compounds of formula A: Formula (1) pharmaceutically acceptable salts thereof are described, which selectively inhibit Raf kinase activity and are useful for treating disorders mediated by Raf kinases.

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Quinuclidine – Wikipedia,
Quinuclidine | C7H18N | ChemSpider

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Preparation of S-(-)- and R-(+)-N-(quinuclidinyl-3)-amide

Optical active forms of the carboxylic acid amines of 3-aminoquinuclidine of formula (I), and the preparation thereof. These can be hydrolysed to the optical active forms of 3-aminoquinuclidine.

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Quinuclidine – Wikipedia,
Quinuclidine | C7H112N | ChemSpider

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Method of treating or preventing schizophrenia and/or psychosis using S-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamides

Compounds of general formula I STR1 wherein: X represents oxygen or sulphur; each of R1 and R3 independently represents hydrogen or a C1 -C4 alkyl group; Ar represents: a phenyl ring optionally substituted by one, two or three C1 -C4 alkoxy groups and/or by one or two halogen atoms; a phenyl ring of the general formula STR2 wherein R2 represents halogen, 4,5-benzo, C1 -C8 alkoxy, C1 -C4 alkylcarbonyl or Am, wherein Am represents amino, methylamino or dimethylamino, R4 represents C1 -C8 alkyl, n is 1 or 2; or a pyrimidinyl moiety of the general formula STR3 wherein R5 is C1 -C4 alkyl; and their N-oxides and pharmaceutically acceptable salts are useful as antischizophrenic and/or antipsychotic agents. A preferred compound is S(-)-4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide.

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Quinuclidine – Wikipedia,
Quinuclidine | C7H124N | ChemSpider

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NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS

Compounds of formula (I), wherein D, Ar1, E and Ar2 are as defined in the specification, processes for preparing them, pharmaceutical compositions containing them and their use in therapy, especially in the treatment or prophylaxis of psychotic and intellectual impairment disorders.

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Quinuclidine – Wikipedia,
Quinuclidine | C7H106N | ChemSpider

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Novel potent 5-HT3 receptor ligands based on the pyrrolidone structure: Synthesis, biological evaluation, and computational rationalization of the ligand-receptor interaction modalities

Novel conformationally constrained derivatives of classical 5-HT3 receptor antagonists were designed and synthesized with the aim of probing the central 5-HT3 receptor recognition site in a systematic way. The newly-synthesized compounds were tested for their potential ability to inhibit [3H]granisetron specific binding to 5-HT3 receptor in rat cortical membranes. These studies revealed subnanomolar affinity in some of the compounds under study. The most potent ligand in this series was found to be quinuclidine derivative (S)-7i, which showed an affinity comparable with that of the reference ligand granisetron. The potential 5-HT3 agonist/antagonist activity of some selected compounds was assessed in vitro on the 5-HT3 receptor-dependent [14C]guanidinium uptake in NG 108-15 cells. Both of the tropane derivatives tested in this functional assay (7a and 9a) showed antagonist properties, while the quinuclidine derivatives studied [the enantiomers of compounds 7i, 8g, and 9g, and compound (R)-8h] showed a full range of intrinsic efficacies. Therefore, the functional behavior of these 5-HT3 receptor ligands appears to be affected by the structural features of both the azabicyclo moiety and the heteroaromatic portion. In agreement with the data obtained on NG 108-15 cells, investigations on the 5-HT3 receptor-dependent Bezold-Jarisch reflex in urethane-anaesthetized rats confirmed the 5-HT3 receptor antagonist properties of compounds 7a and (S)-7i showing for these compounds ID50 values of 2.8 and 181 mug/kg, respectively. Finally, compounds 7a, (S)-7i and 9a (at the doses of 0.01, 1.0, and 0.01 mg/kg ip, respectively) prevented scopolamine-induced amnesia in the mouse passive avoidance test suggestive of a potential usefulness in cognitive disorders for these compounds. Qualitative and quantitative structure-affinity relationship studies were carried out by means of theoretical descriptors derived on a single structure and ad-hoc defined size and shape descriptors (indirect approach). The results showed to be useful in capturing information relevant to ligand-receptor interaction. Additional information derived by the analysis of the energy minimized 3-D structures of the ligand-receptor complexes (direct approach) suggested interesting mechanistic and methodological considerations on the binding mode multiplicity at the 5-HT3 receptors and on the degree of tolerance allowed in the alignment of molecules for the indirect approach, respectively.

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Quinuclidine – Wikipedia,
Quinuclidine | C7H140N | ChemSpider

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Muscarinic receptor agonists, like dopamine receptor antagonist antipsychotics, inhibit conditioned avoidance response in rats

The purpose of our studies was to determine the effects of muscarinic receptor agonists on conditioned avoidance responding in the rat. Rats were trained to avoid or escape an electric shock delivered to the feet in a discrete trial procedure. The muscarinic receptor agonists pilocarpine and [2-ethyl-8-methyl-2,8-diazaspiro(4.5)decane-1,3-dione] hydrochloride (RS86) and the cholinesterase inhibitor physostigmine all decreased the percentage of avoidance responses at doses that produced less than approximately 30% response failures. Similar results were obtained with the antipsychotic drugs haloperidol, trifluoperazine, chlorpromazine, and clozapine. However, the benzodiazepine anxiolytic diazepam did not decrease avoidance responding up to doses that produced ataxia. On the other hand, oxotremorine and arecoline decreased avoidance responding only by producing response failures, whereas aceclidine produced intermediate changes. The muscarinic receptor antagonists scopolamine, trihexyphenidyl, and benztropine were without effect when administered alone but antagonized the decreases in avoidance responding produced by pilocarpine and RS86. Scopolamine had little effect on the decreases in avoidance responding produced by haloperidol. The newer muscarinic receptor partial agonists or agonist/antagonists [R-(Z)-(+)-alpha- (methoxyimino)-1-azabicyclo[2.2.2]octane-3-acetonitrile] hydrochloride, talsaclidine, milameline, and xanomeline also produced dose-related decreases in avoidance responding. Our results demonstrate that muscarinic receptor agonists can decrease avoidance responding in a manner similar to dopamine- receptor antipsychotic drugs, suggesting that muscarinic receptor agonists may provide an alternative approach to the treatment of psychosis.

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Quinuclidine – Wikipedia,
Quinuclidine | C7H81N | ChemSpider

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Synthesis of the optical isomers of a new anticholinergic drug, penehyclidine hydrochloride (8018)

A practical diastereoselective synthetic method for 8018 enantiopure isomers is described. The intramolecular asymmetric epoxidation of mono-sulfonate 4 was applied for the execution of the synthesis of the key chiral building block for the first time. The isomers were obtained with 70-76% yields in 99-100% ee.

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Quinuclidine – Wikipedia,
Quinuclidine | C7H60N | ChemSpider

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Ophthalmic formulation of a selective cyclooxygenase-2 inhibitory drug

There is provided a pharmaceutical composition suitable for topical administration to an eye which contains a selective COX-2 inhibitory drug or nanoparticles of a drug of low water solubility, in a concentration effective for treatment and/or prophylaxis of a disorder in the eye, and one or more ophthalmically acceptable excipients that reduce rate of removal from the eye such that the composition has an effective residence time of about 2 to about 24 hours. Also provided is a method of treating and/or preventing a disorder in an eye, the method comprising administering to the eye a composition of the invention.

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Quinuclidine | C7H44N | ChemSpider

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Muscarinic effects on cellular functions in cultured human ciliary muscle cells

Purpose. To characterize the pharmacology of the carbachol-induced changes of phospholipase C (PLC) activity and intracellular calcium concentration ([Ca2+](i)) in cultured human ciliary muscle cells. Methods. Changes in PLC activity of cultured human ciliary muscle cells were determined by production of inositol phosphates. Single-cell dynamic fluorescence ratio imaging was used to determine [Ca2+](i). Results. Carbachol, oxotremorine-M, aceclidine, and pilocarpine stimulated PLC with mean EC50s of 20, 8, 17, and 2 muM, respectively. The effect of carbachol on PLC was partially suppressed by extracellular Ca2+ depletion. This muscarinic effect was blocked by muscarinic antagonists, such as atropine (apparent pK(i) = 9.12, nonselective for muscarinic receptor subtypes), pirenzepine (pK(i) = 6.76, selective for the M1 receptor subtype), 4DAMP (pK(i) = 9.25, selective for the M1 and M3 subtypes), and fHHSiD (pK(i) = 7.77, selective for the M3 subtype). In [Ca2+](i) experiments, carbachol increased [Ca2+](i) transients in human ciliary muscle cells in a dose-dependent manner with a mean EC50 of 7 muM. 4DAMP was approximately 100 times more potent than pirenzepine in the inhibition of the carbachol-induced [Ca2+](i) increase. [Ca2+](i) oscillations were observed after carbachol stimulation and persisted after extracellular Ca2+ depletion. Conclusions. Muscarinic agonists activate PLC and increase [Ca2+](i) in cultured human ciliary muscle cells through an M3-like muscarinic receptor subtype.

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Quinuclidine – Wikipedia,
Quinuclidine | C7H71N | ChemSpider

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4-SUBSTITUTED IMIDAZOLES

Compounds of formula I: wherein A and R1 are as defined in the specification, processes for preparing them, pharmaceutical compositions containing them and their use in therapy, especially in the treatment or prophylaxis of psychotic and intellectual impairment disorders.

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Quinuclidine – Wikipedia,
Quinuclidine | C7H103N | ChemSpider