Extracurricular laboratory:new discovery of (R)-3-Aminoquinuclidine dihydrochloride

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Design, synthesis, structure-activity relationship, and in vivo activity of azabicyclic aryl amides as alpha7 nicotinic acetylcholine receptor agonists

A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed alpha7 nAChR agonist, PNU-282,987, while maintaining the compound’s other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.

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2-substituted benzamide and benzoate derivatives of 3-aminoquinuclidine and 3-quinuclidinol

This invention provides novel 3-quinuclidinyl benzamides and benzoates which have utility as therapeutical agents which exhibit anxiolytic, antipsychotic, cognition improvement, antiemetic and gastric prokinetic effects in warm blooded animals. The compounds useful in the methods and composition of this invention are represented by the formula: STR1 where X is oxygen or sulfur; Y is –NH or –O–; when Y is –O–, R1 is STR2 and when Y is –NH, R1 is STR3 and R2 is hydrogen, C1 -C4 alkyl or C1 -C4 alkenyl; the geometrical and optical isomers, or a pharmaceutically acceptable salt thereof.

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SUBSTITUTED SPIRO-AMIDE COMPOUNDS

Substituted spiro-amide compounds corresponding to formula 1 in which R5 through R8, D, X, Y and Z have defined meanings, processes for preparing such spiro-amide compounds, pharmaceutical compositions containing such compounds, and methods of using such spiro-amide compounds for treating and/or inhibiting disorders or disease states mediated at least in part by the bradykinin 1 receptor

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Synthetic Route of 123536-14-1, Catalysts function by providing an alternate reaction mechanism that has a lower activation energy than would be found in the absence of the catalyst. In some cases, the catalyzed mechanism may include additional steps.In a article, 123536-14-1, molcular formula is C7H16Cl2N2, introducing its new discovery.

COMPOUNDS HAVING BOTH ALPHA-7 NICOTINIC AGONIST ACTIVITY AND 5HT3 ANTAGONIST ACTIVITY FOR TREATMENT OF CNS DISEASES

The invention discloses compounds that are selective alpha7 nAChR agonists and 5-HT3 antagonists. The compounds are useful for treating many CNS diseases.

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Azabicyclic compounds for the treatment of disease

The invention provides compounds of Formula I: 1wherein Azabicyclo is 2W is a six-membered heterocyclic ring system having 1-2 nitrogen atoms or a 10-membered bicyclic-six-six-fused-ring system having up to two nitrogen atoms within either or both rings, provided that no nitrogen is at a bridge of the bicyclic-six-six-fused-ring system, and further having 1-2 substitutents independently selected from R3. These compounds may be in the form of pharmaceutical salts or compositions, may be in pure enantiomeric form or racemic mixtures, and are useful in pharmaceuticals to treat diseases or conditions in which alpha7 is known to be involved.

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PHARMACEUTICAL COMPOUNDS

The invention relates to compounds and compositions for inhibiting the enzyme fatty acid amide hydrolase (FAAH), the use of the compounds in therapy and, in particular, for treating or preventing conditions whose development or symptoms are linked to substrates of the FAAH enzyme, and methods of treatment or prevention using the compounds and compositions.

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Synthesis of quinazoline-2,4-dione and naphthalimide derivatives as new 5-HT3 receptor antagonists

New potent 5-HT3 receptor antagonists have been designed from the naphthalimide moiety and a quinuclidine heterocycle and the structure-activity relationships are discussed here on the basis of the nature of the substituent on the aromatic system. The biological activity of the compounds was evaluated in binding assays with [3H]BRL-43694 and by inhibition of the Bezold-Jarisch reflex. Compound 22 with a 4-amino substituent was equipotent to the reference compounds. In contrast to the benzamide derivatives, the activity resides essentially in the (R) enantiomer (K(i) = 0.15 ¡À 0.05 nM, ID50 = 1.6 mug/kg/iv) and it is demonstrated that the additional carbonyl group is involved in the inversion of the enantioselectivity of the receptor. Conformational studies of (R)-22 demonstrated the presence of a locked structure with 4 minimal energy conformers which were compared to those of (S)-zacopride. The superimposition of the putative active conformers emphasized the presence of a second polar group in the binding site. The fluorescent properties of the compounds were studied and indicate that (R)-22 and its derivatives may be promising tools for the direct visualization of 5-HT3 receptors.

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Discovery of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5- carboxamide, an agonist of the alpha7 nicotinic acetylcholine receptor, for the potential treatment of cognitive deficits in schizophrenia: Synthesis and structure-activity relationship

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia. Compound 14 is a potent and selective a7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory sensory gating and, in an in vivo model to assess cognitive performance, novel object recognition.

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[…] aromatic system amide derivative and its preparation and use (by machine translation)

The invention discloses a […] aromatic system amide derivatives, its general formula (I) is shown, wherein the R, W1 , W2 , W3 , W4 See the specification. In addition, the invention also discloses a method for preparation of the above compounds, pharmaceutical composition. The invention relates to a compound has good alpha 7 receptor binding activity, higher selectivity and high levels of agonist effect. (by machine translation)

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Directed synthesis of noncentrosymmetric molybdates using composition space analysis

A systematic investigation of the factors governing the reaction product composition, hydrogen bonding, and symmetry was conducted in the MoO 3/3-aminoquinuclidine/H2O system. Composition space analysis was performed through 36 individual reactions under mild hydrothermal conditions using racemic 3-aminoquinuclidine. Single crystals of three new compounds, [C7H16N2][Mo 3O10]¡¤H2O, [C7H 16N2]2[Mo8O26] ¡¤H2O, and [C7H16N2] 2[Mo8O26]¡¤4H2O, were grown. The relative phase stabilities for these products are dependent upon the reactant mole fractions in the initial reaction gel. This phase stability information was used to direct the synthesis of two new noncentrosymmetric compounds, using either (S)-(-)-3-aminoquinuclidine dihydrochloride or (R)-(+)-3-aminoquinuclidine dihydrochloride. [(R)-C7H 16N2]2-[Mo8O26] and [(S)-C7H16N2]2[Mo8O 26] both crystallize in the noncentrosymmetric space group P2 1 (No. 4), which has the polar crystal class 2 (C2). The second-harmonic generation activities were measured on sieved powders. The structure-directing properties of the molybdate components in each compound were determined using bond valence sums. The structures of all five compounds were determined using single-crystal X-ray diffraction.

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