WO1994007489A1 - Inhibiteurs non competitifs de recepteurs neuronaux de l'acetylcholine nicotinique - Google Patents

Inhibiteurs non competitifs de recepteurs neuronaux de l'acetylcholine nicotinique Download PDF

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Publication number
WO1994007489A1
WO1994007489A1 PCT/US1993/009050 US9309050W WO9407489A1 WO 1994007489 A1 WO1994007489 A1 WO 1994007489A1 US 9309050 W US9309050 W US 9309050W WO 9407489 A1 WO9407489 A1 WO 9407489A1
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bis
alkyl radical
sebacate
range
piperidinyl
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PCT/US1993/009050
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English (en)
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Roger L. Papke
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The Salk Institute For Biological Studies
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/625—Salicylic acid; Derivatives thereof having heterocyclic substituents, e.g. 4-salicycloylmorpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine

Definitions

  • the present invention relates to methods for the non-competitive inhibition of neuronal nicotinic acetylcholine receptors, as well as compounds and compositions which are useful for such purpose.
  • neurotransmitter(s) In the nervous system, signals are passed from one cell (neuron) to another through the local release (at synapses) of neurotransmitter(s).
  • Two of the most important neurotransmitters are acetylcholine (ACh) and glutamate, both having rapid excitatory effects on other cells.
  • ACh acetylcholine
  • glutamate Two of the most important neurotransmitters are acetylcholine (ACh) and glutamate, both having rapid excitatory effects on other cells.
  • ACh acetylcholine
  • glutamate Two of the most important neurotransmitters are acetylcholine (ACh) and glutamate, both having rapid excitatory effects on other cells.
  • ACh acetylcholine
  • glutamate glutamate
  • Each membrane-bound receptor is a complex of several protein subunits.
  • AChRs acetylcholine receptors
  • Each different type of receptor has different functional properties and a characteristic subunit composition.
  • AChR generates the stimulation of muscle cells
  • another subtype mediates transmission through autonomic ganglia
  • other subtypes which are involved in nicotine addiction, are found in the brain.
  • the techniques of molecular biology have been used to clone numerous AChR subunit genes. This has enabled the expression of these genes in cells which are easily accessible for experimental manipulation.
  • AChRs may be studied by expressing the genes encoding particular AChR subunit combinations in frog oocytes.
  • the members of the family of nicotinic acetylcholine receptor genes encode subunits of acetylcholine receptors found in muscle cells ( ⁇ 1, ⁇ 1 , ⁇ , ⁇ and ⁇ ), as well as subunits of nicotinic acetylcholine receptors found in the central and peripheral nervous system.
  • the neuronal nicotinic receptor genes shown to form functional receptors when expressed in Xenopus oocytes include a subset of genes which encode putative neuronal alpha subunits (i.e., ⁇ 1, ⁇ 3, ⁇ 4 and ⁇ 7), based on the similarities of their deduced amino acid sequences to that of the muscle receptor receptor alpha subunit ( ⁇ 1) in the region believed to contain part of the agonist binding site. Additionally, two genes known to encode functional neuronal nicotinic beta subunits (i.e., ⁇ 2 and ⁇ 4 ) have also been cloned. In general, the ⁇ 2, ⁇ 3 and ⁇ 4 subunits do not form functional receptors by themselves.
  • ligand-gated ion channels These receptor complexes are, therefore, referred to as ligand-gated ion channels, and are involved in various forms of drug interactions. Drugs which bind to the same site as the endogenous activating ligand are said to have competitive effects. Drugs which affect function by binding to other sites are referred to as non-competitive agents. It is presently believed that some non-competitive inhibitors bind to sites directly in the ion channel, and have full access to their respective binding sites only when the ion channel is open.
  • non-competitive inhibitors that bind to sites directly in the ion channel are, therefore, capable of modulating the effect of receptor agonists only when the presence of agonist has caused the ion channel to open.
  • the greater the activating effect of a given receptor agonist the greater the access of the non-competitive inhibitor to the ion channel.
  • the present invention is directed to the identification of a class of compounds which are selective non-competitive and use-dependent inhibitors for neuronal nicotinic acetylcholine receptors.
  • inventions which function as selective non-competitive inhibitors of neuronal nicotinic acetylcholine receptors.
  • Invention compounds are highly specific for neuronal nicotinic acetylcholine receptors, blocking receptors only after their activation by agonists (such as endogenous acetylcholine or an exogenously supplied stimulant such as nicotine).
  • the invention compounds can be administered in a variety of ways, for example, by way of porous subcutaneous implants, transdermally, and the like, and can be used to treat a variety of conditions, such as habituated tobacco users (e.g., smokers or chewers), or in other circumstances where a therapeutic down-regulation of autonomic activity is desired (e.g., treatment of hypertension).
  • habituated tobacco users e.g., smokers or chewers
  • a therapeutic down-regulation of autonomic activity e.g., treatment of hypertension.
  • Figure 1 presents voltage clamp recordings from oocytes injected with RNA encoding the neuronal nicotinic AChR subunits ⁇ 3 and ß4.
  • Figure 2 summarizes the effect of various concentrations of invention compound I on the responses of ⁇ 3ß4 injected oocytes.
  • Figure 3A presents voltage clamp recordings from oocytes injected with RNA encoding neuronal nicotinic AChR subunits ⁇ 3 and ß4 in response to acetylcholine before, during and after co-application of invention compound I.
  • Figures 3B and 3C illustrate the fact that the effects of invention compound I require co-application of agonist along with invention compound I.
  • Figure 4 illustrates the blockage of muscle receptor subunit combinations by exposure to invention compound I.
  • Figure 5 is a pictorial representation of the conformational states of neuronal nicotinic AChR.
  • a method to inhibit the action of neuronal nicotinic acetylcholine receptors comprising contacting said receptor(s) with an effective amount of at least one compound having the structure:
  • each R is independently selected from H or a C 1 -C 12 alkyl radical, with the proviso that at least one R group on each of C ⁇ and C ⁇ is not H; preferably each R is independently selected from a C 1 -C 4 alkyl radical; with a presently preferred species having all R groups being either a methyl or ethyl radical;
  • R 1 is selected from H, a C 1 -C 12 alkyl radical, or a C 4 -C 12 alicyclic or alkyl substituted alicyclic radical; preferably R 1 is selected from H or a C 1 -C 6 alkyl radical; with R 1 of presently preferred species being H or a methyl or ethyl radical;
  • each Z is independently selected from - O -,
  • Z' is selected from or , with the
  • R 2 is selected from H or a C 1 -C 12 alkyl radical; preferably R 2 is selected from H or a C 1 -C 6 alkyl radical; with R 2 of presently preferred species being H or a methyl radical;
  • X is selected from:
  • each R 3 is independently selected from H or a C 1 -C 12 alkyl radical; preferably R 3 is selected from H or a C 1 -C 6 alkyl radical; with R 3 of presently preferred species being H or a methyl radical;
  • each Y is independently selected from - O -, - S -, or - NR -; preferably, each Y is - O -; each Y' is independently selected from: , , or
  • x is a whole number falling in the range of about 1 up to 20; and preferably x falls in the range of about 2 up to 12;
  • x' is a whole number falling in the range of about 1 up to 12; and preferably x' falls in the range of about 2 up to 8;
  • x" is a whole number falling in the range of about 2 up to 10; and preferably x" falls in the range of about 2 up to 6;
  • y is a whole number falling in the range of about 1 up to 8; preferably y falls in the range of about 2 up to 6;
  • z is a whole number falling in the range of about 0 up to 6; preferably z falls in the range of about 0 up to 4; and
  • Z" is selected from a C 1 up to C 12 alkyl radical, or
  • R, R 1 , Z, n, Z' (and R 2 ) are as defined above,
  • X is selected from:
  • R 3 , Y, Y', x, x', y and z are as defined above; preferably, R 3 is H, Y is - O -, Y' is ; x falls in the range of about 2 up to 12, x' falls in the range of about 2 up to 8, y falls in the range of about 2 up to 6 and z falls in the range of about 0 up to 4.
  • Especially preferred X groups comprise a backbone of at least 6 atoms, wherein the moiety X - Z" is:
  • R, R 1 , R 3 , n and x are as defined above; with an especially preferred embodiment comprising compounds wherein each R is independently selected from a C 1 -C 4 alkyl radical, R is selected from a C 1 -C 6 alkyl radical, R is H, n is 1 and x is 2-12.
  • Z" is selected from:
  • R, R 1 , R 2 , Z, and Z' and n are as defined above; preferably R is a methyl or ethyl radical, R 1 is H or a methyl or ethyl radical, each Z is - CH 2 -, Z' is: (thus R 2 is preferably H), and n is 1.
  • R, R 1 , R 3 , n and x are as defined above.
  • Especially preferred compounds include those having the above- described structure and wherein each R is independently selected from a C 1 -C 4 alkyl radical, R 1 is selected from a C 1 -C 6 alkyl radical, R 3 is H, n is 1 and x is 2-12.
  • Exemplary compounds contemplated for use in the practice of the present invention include 4-stearoyloxy2,2,6,6-tetramethylpiperidine, 1-ethyl-4-salicyloyloxy- 2 , 2 , 6, 6-tetramethylpiperidine, 1, 2 , 2, 6, 6- pentamethylpiperidin-4-yl-ß-(3,5-ditertbutyl-4- hydroxyphenyl) -propionate, (di-2 , 2 , 6 , 6- tetramethylpiperidin-4-yl)-adipate, (di-1,2,3,3,6- tetramethyl-2,6-diethyl-piperidin-4-yl)sebacate, dibutyl- maIonic acid-di-(1,2,2,6,6-pentamethyl-piperidin-4- yl)ester, butyl-(3,5-di-tert-butyl-4-hydroxybenzyl)- malonic acid-di(1,2,2,6,6
  • R is methyl or ethyl and R 1 is H, methyl or ethyl, e.g., bis (2,2,6,6-tetramethyl-4-piperidinyl) sebacate (i.e., invention compound I), bis (2,2,6,6-tetraethyl-4-piperidinyl) sebacate, bis (1,2,2,6,6-pentamethyl-4-piperidinyl) sebacate, bis (1,2,2,6,6-pentaethyl-4-piperidinyl) sebacate, bis (1-methyl-2,2,6,6-tetraethyl-4-piperidinyl) sebacate, bis (1-ethyl-2,2,6,6-pentamethyl-4-piperidinyl) sebacate, and the like.
  • bis (2,2,6,6-tetramethyl-4-piperidinyl) sebacate i.e., invention compound I
  • invention compounds on neuronal nicotinic acetylcholine receptors are only slowly reversible. While the onset of signal inhibition depends on the level of receptor activation, the slow dissociation of invention compounds from the receptor is independent of agonist. This suggests that an equilibrium relationship will be reached in the continued presence of low concentrations of invention compounds, and that the extent of equilibrium down-regulation of receptor function would depend on the amount of receptor activation. Thus, a higher level of activation would lead to a greater degree of inhibition by invention compounds. Therefore, low levels of invention compounds will buffer the effects of nicotine as it stimulates receptor activation, leading to a blockade of the behavioral and addictive effects of this drug.
  • Tobacco use (such as smoking or chewing) is a learned behavior in which the processes of tobacco consumption become associated with the effects of nicotine on the nervous system. If low concentrations of invention compounds break this pattern of association (by diminishing nicotinic receptor activation subsequent to tobacco consumption), it should be possible for a smoker (or tobacco chewer) to more readily abandon the tobacco habit.
  • the phrase "inhibit the action of neuronal nicotinic acetylcholine receptors" refers to the use-dependent blockade, caused by invention compounds, of ion conduction through channels formed by neuronal nicotinic acetylcholine receptors.
  • channels formed by neuronal nicotinic acetylcholine receptors are opened upon exposure to neurotransmitters, in the further presence of invention compounds, the resulting ability of ions to flow through the channel is blocked.
  • FIG. 5 a pictorial representation of the conformational states which are believed to be assumed by neuronal nicotinic AChR is presented in Figure 5.
  • Component R in the Figure represents the receptor subunit complex in the closed channel conformation
  • component AR* represents channels in the open state (which is required for a noncompetitive blockage site to be available)
  • component AR*T represents open channels blocked by a non-competitive inhibitor (such as invention compound I)
  • component R ⁇ T represents receptors in a blocked intermediate state in which the receptor remains blocked in the absence of agonist.
  • Receptor(s) to be contacted with invention compound is provided by a variety of sources, e.g., by cells expressing said receptor(s); by membranes containing said receptor; by channels formed by said receptor(s); and the like.
  • an effective amount when used in reference to compounds of the invention, refers to levels of compound sufficient to provide circulating concentrations high enough to effect a down-regulation of neuronal nicotinic acetylcholine receptor function, without substantially compromising other transmitter systems. Such a concentration typically falls in the range of about 10 nM up to 2 ⁇ M; with concentrations in the range of about 100 nM up to 200 nM being preferred.
  • a method to block the ion channel defined by a neuronal nicotinic acetylcholine receptor when said receptor has been activated by an agonist therefor comprising contacting said channel with an effective amount of at least one hindered amine compound as described above.
  • a method for reducing the neurological effects of nicotine in a subject addicted thereto comprising administering to a subject, while said subject self-administers or is exposed to tobacco, an effective amount of at least one hindered amine compound as described above.
  • compositions comprising at least one hindered amine compound as described above, and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers contemplated for use in the practice of the present invention include carriers suitable for oral, intravenous, subcutaneous, intramuscular, intracutaneous, and the like administration. Administration in the form of creams, lotions, tablets, dispersible powders, granules, syrups, elixirs, sterile aqueous or non-aqueous solutions, suspensions or emulsions, and the like, is contemplated.
  • suitable carriers include emulsions, solutions, suspensions, syrups, and the like, optionally containing additives such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents, and the like.
  • suitable carriers include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • suitable carriers include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
  • Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions.
  • invention compounds can also be manufactured in the form of sterile water, or some other sterile injectable medium immediately before use.
  • Invention compound can also be formulated with a carrier that prevents rapid release therefrom.
  • invention compound may be formulated in gels or suspensions with a protective non-antigenic hydrocolloid, for example, sodium carboxymethy lcellulose, polyvinylpyrrolidone, sodium alginate, gelatin, polygalacturonic acids, for example, pectin, or certain mucopolysaccharides, together with aqueous or non-aqueous pharmaceutically acceptable liquid vehicles, preservatives, or surfactants.
  • a protective non-antigenic hydrocolloid for example, sodium carboxymethy lcellulose, polyvinylpyrrolidone, sodium alginate, gelatin, polygalacturonic acids, for example, pectin, or certain mucopolysaccharides, together with aqueous or non-aqueous pharmaceutically acceptable liquid vehicles, preservatives, or
  • Such formulations, as well as suspensions of compounds which are only sparingly soluble in body fluids are slowly released into the blood stream, and are preferably administered by intramuscular injection.
  • some of the solid dosage forms listed above, for example, certain sparingly water-soluble compounds for example, dispersions in a neutral hydrogel of a polymer of ethylene glycol methacrylate or similar monomers cross-linked as described in U.S. Patent No. 3,551,556 may also be formulated in the form of slow-release pellets, and may be implanted subcutaneously or intramuscularly.
  • Data were obtained by means of two electrode voltage clamp recording, using an Axoclamp 2A amplifier. Recordings were made at room temperature (21-24°C) in Frog Ringers (115 mM NaCl, 10 mM HEPES, 2.5 mM KCl, and 1.8 mM CaCl 2 , pH 7.3) with 1 ⁇ M atropine.
  • the current electrode solution was 250 mM CsCl, 250 mM CsF, and 100 mM EGTA, pH 7.3, and the voltage electrode was filled with 3M KCl.
  • Fresh acetylcholine (Sigma) stock solutions were made daily in Ringers and diluted. Electrodes were fabricated from Dagan FLG 15 glass capillary tubes. The resistance of voltage electrodes was on the order of 3 to 9 M ⁇ , and current electrodes were between 0.5 and 3 m ⁇ , usually around 1 M ⁇ .
  • Oocytes were placed in a lucite chamber having a total volume capacity of 0.5 ml. Bath solution and drug applications were delivered through a linear bath perfusion system. Drug delivery involved preloading a 1.8 ml length of tubing at the terminus of the perfusion system by various means. A Mariotte flask filled with Ringers was used to maintain a constant hydrostatic pressure for drug deliveries and washes. With this system, the agonist and antagonist application pulses were consistent in both volume and duration. Current responses were recorded on a Gould chart recorder and peak currents also measured with a digital meter in parallel to the amplifier output. Except where otherwise noted, a holding potential of -70 mV or -50 mV was applied.
  • the basic protocol employed for all experiments described in Figure 1 involved the measurement of current responses of oocytes injected with RNA encoding neuronal nicotinic AChR subunits ⁇ 3 and ß4 to the application of agonist-containing solutions at intervals of 5 minutes.
  • Data in the Figure are normalized to the initial responses of the individual oocytes to a control application of ACh 5 minutes prior to experimental applications. Recovery was evaluated from the responses to additional agonist applications following periods of wash by control Ringer solution. Shown in the Figure are the current responses to the brief application of 30 ⁇ M ACh, bath applied at 5 minute intervals. In all cases, the first and third responses are to the application of ACh alone, loaded into the perfusion system from a control reservoir.
  • the second responses represent the effects of 30 ⁇ M ACh plus increasing concentrations of invention compound I (B-D), loaded in the same manner as the control solution (A).
  • B-D control solution
  • a dilute stock solution of invention compound I was prepared, since the compound is not 100% soluble at 100 ⁇ g/ml, but does appear fully dissolved at 10 ⁇ g/ml.
  • Responses to the application of increasing concentrations of invention compound I are illustrated in Figures 1 and 2.
  • Figure 2 shows the effect of various concentrations of invention compound I on the responses of ⁇ 3ß4 injected oocytes. Represented are the average normalized responses ( ⁇ SEM) of three ⁇ 3ß4 injected oocytes to the co-application of:
  • the response of each oocyte was normalized to its response to 30 ⁇ M ACh applied 5 minutes prior to the co-applications represented in the figure.
  • the right cluster of bars represents the normalized responses after a 5 minute wash period.
  • a 200 nM solution produced an inhibition approximately 50% of the control response after the 5 minute wash, while a 2 ⁇ M solution produced 50% inhibition during the co-application, and a reduction to ⁇ 10% of control levels when evaluated after the wash period.
  • the presence of 20 ⁇ M of invention compound I in the agonist solution reduced responses during the co-application to values less than 10% of the control response, with less than 3% of the initial response observed after the 5 minute wash period when control solutions were delivered from reservoirs.
  • Figure 3 presents voltage clamp recordings from oocytes injected with RNA encoding the neuronal nicotinic AChR subunits ⁇ 3 and ß4. Shown in Figure 3A are the current responses to 30 ⁇ M ACh before (trace 1), during (trace 2) and after (trace 3) co-application of 20 ⁇ M of invention compound I. The insert shows the same three responses in the main figure, scaled to the same peak amplitude. The bar represents the period of agonist application. The current responses of two brief bath applications of 30 ⁇ M ACh loaded into the perfusion system from a control reservoir are shown in Figures 3B and 3C. In Figure 3B, 5 minutes after the initial response a control (blank) solution was loaded and applied.
  • FIG. 4B illustrates the inhibition of ⁇ 1 ⁇ 2 ⁇ receptors by a 2 ⁇ M solution of invention compound I.
  • the cluster of bars on the left represents the average normalized responses ( ⁇ SEM) of ⁇ 1 ⁇ 2 ⁇ injected oocytes to the application of 10 ⁇ M ACh alone (striped bars) or 10 ⁇ M ACh plus invention compound I (striped, shaded bars).
  • the right cluster of bars represents the normalized responses after a five minute wash.
  • Figure 4C illustrates the inhibition of ⁇ 1 ⁇ 4 ⁇ receptors by a 2 ⁇ M solution of invention compound I.
  • the cluster of bars on the left represents the average normalized responses ( ⁇ SEM) of ⁇ 1 ⁇ 4 ⁇ injected oocytes to the application of 10 ⁇ M ACh alone (striped bars) or 10 ⁇ M ACh plus invention compound I (striped, shaded bars).
  • the right cluster of bars represents the normalized responses after a five minute wash.
  • invention compounds are seen to be potent inhibitors of all of the functional pair-wise combinations of neuronal nicotinic receptor subunits as shown in Table III.
  • Invention compound I was effective at inhibiting all subunit combinations when oocytes were injected with RNAs encoding ⁇ 2 + ß2, ⁇ 2 + ß4, ⁇ 2 + ß2, ⁇ 4 + ß2 or ⁇ 4 + ß4 subunits.
  • the rate of recovery from inhibition was slow for all of these subunit combinations and was in fact too slow to estimate for ⁇ 2ß2 and ⁇ 3ß2 receptors.

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Abstract

L'invention concerne une nouvelle catégorie de composés fonctionnant en tant qu'inhibiteurs sélectifs non compétitifs de récepteurs neuronaux de l'acétylcholine nicotinique, ainsi que des compositions contenant lesdits composés. Ces composés sont extrêmement spécifiques contre des récepteurs neuronaux de l'acétylcholine nicotinique, ne bloquant lesdits récepteurs qu'après leur activation par des agonistes. Sont également décrits des procédés visant à inhiber l'action de récepteurs neuronaux de l'acétylcholine nicotinique, ainsi que des procédés servant à limiter les effets neurologiques de la nicotine chez un sujet dépendant.
PCT/US1993/009050 1992-10-02 1993-09-24 Inhibiteurs non competitifs de recepteurs neuronaux de l'acetylcholine nicotinique WO1994007489A1 (fr)

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WO1997019059A1 (fr) * 1995-11-17 1997-05-29 Sibia Neurosciences, Inc. Nouveaux composes d'aryle substitues utiles comme modulateurs des recepteurs de l'acetylcholine
US5817679A (en) * 1993-04-01 1998-10-06 University Of Virginia 7-Azabicyclo 2.2.1!-heptane and -heptene derivatives as cholinergic receptor ligands
WO2000006546A1 (fr) * 1998-07-30 2000-02-10 The Picower Institute For Medical Research Compositions pharmaceutiques immunotherapeutiques anticancereuses
US6060473A (en) * 1993-04-01 2000-05-09 Ucb S.A. - Dtb 7-azabicyclo[2.2.1]-heptane and -heptene derivatives as cholinergic receptor ligands
US6077846A (en) * 1993-09-10 2000-06-20 Ucb, S.A. Epibatidine and derivatives thereof as cholinergic receptor agonists and antagonists
US6117889A (en) * 1994-04-01 2000-09-12 University Of Virginia 7-Azabicyclo-[2.2.1]-heptane and -heptene derivatives as analgesics and anti-inflammatory agents
US6242448B1 (en) 1998-12-17 2001-06-05 American Home Products Corporation Trisubstituted-oxazole derivatives as serotonin ligands
US6248356B1 (en) 1997-06-13 2001-06-19 The Picower Institut For Medical Research Immunotherapeutic anti-cancer pharmaceutical compositions
WO2005032479A2 (fr) * 2003-10-01 2005-04-14 Unviversity Of Florida Research Foundation, Inc. Compositions et methodes d'inhibition selective des recepteurs nicotiniques de l'acetylcholine
US20160060528A1 (en) * 2014-09-02 2016-03-03 Merck Patent Gmbh Compounds and liquid-crystalline medium
DE102015013980A1 (de) 2014-11-11 2016-05-12 Merck Patent Gmbh Heterocyclische Verbindung, Flüssigkristallines Medium, Methode zu seiner Stabilisierung und Fküssigkristallanzeige

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6255490B1 (en) 1993-04-01 2001-07-03 University Of Virginia 7-azabicyclo[2.2.1]-heptane and -heptene derivatives as cholinergic receptor ligands
US5817679A (en) * 1993-04-01 1998-10-06 University Of Virginia 7-Azabicyclo 2.2.1!-heptane and -heptene derivatives as cholinergic receptor ligands
US6060473A (en) * 1993-04-01 2000-05-09 Ucb S.A. - Dtb 7-azabicyclo[2.2.1]-heptane and -heptene derivatives as cholinergic receptor ligands
US6077846A (en) * 1993-09-10 2000-06-20 Ucb, S.A. Epibatidine and derivatives thereof as cholinergic receptor agonists and antagonists
US6177451B1 (en) 1993-09-10 2001-01-23 Ucb, S.A. Epibatidine and derivatives thereof as nicotine cholinergic receptor agonists
US6117889A (en) * 1994-04-01 2000-09-12 University Of Virginia 7-Azabicyclo-[2.2.1]-heptane and -heptene derivatives as analgesics and anti-inflammatory agents
WO1997019059A1 (fr) * 1995-11-17 1997-05-29 Sibia Neurosciences, Inc. Nouveaux composes d'aryle substitues utiles comme modulateurs des recepteurs de l'acetylcholine
US6482833B2 (en) * 1997-06-13 2002-11-19 North Shore - Long Island Jewish Research Institute Immunotherapeutic anti-cancer pharmaceutical compositions
US6248356B1 (en) 1997-06-13 2001-06-19 The Picower Institut For Medical Research Immunotherapeutic anti-cancer pharmaceutical compositions
WO2000006546A1 (fr) * 1998-07-30 2000-02-10 The Picower Institute For Medical Research Compositions pharmaceutiques immunotherapeutiques anticancereuses
US6242448B1 (en) 1998-12-17 2001-06-05 American Home Products Corporation Trisubstituted-oxazole derivatives as serotonin ligands
WO2005032479A2 (fr) * 2003-10-01 2005-04-14 Unviversity Of Florida Research Foundation, Inc. Compositions et methodes d'inhibition selective des recepteurs nicotiniques de l'acetylcholine
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