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Nicotinic receptor agonists for the treatment of inflammatory diseases

A technology for inflammatory diseases and nicotinic receptors, which is applied in some continuation applications and can solve problems such as low efficacy

Active Publication Date: 2007-07-18
UNIV LAVAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] Similarly, although corticosteroids and other immunosuppressant drugs are routinely used to treat pulmonary fibrosis, they have been shown to be only minimally efficacious (47)

Method used

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  • Nicotinic receptor agonists for the treatment of inflammatory diseases
  • Nicotinic receptor agonists for the treatment of inflammatory diseases
  • Nicotinic receptor agonists for the treatment of inflammatory diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment I

[0348] In Vivo HP Study-I-Hypersensitivity-Like Inflammation

[0349] Effects of nicotinic agonists on chronically induced hypersensitivity pneumonitis (HP) in mice.

[0350] Stimulation of nicotinic receptors with nicotine was demonstrated to down-regulate immune responses to HP antigens through inhibition of inflammatory cytokines and inhibition of specific antigen-mediated cell activation.

[0351] As mentioned above, this model was chosen because the incidence of HP is lower in smokers than in nonsmokers (50), and because the model is well described. HP was induced by administration of an HP form of farmer's lung pathogen Saccharopolyspora straight comma (SR) antigen (51). Mice were also treated with intraperitoneal (IP) nicotine at doses ranging from 0.5-2.0 mg / kg twice a day. Nicotine administration significantly reduced the overall cell numbers found in the bronchoalveolar lavage (BAL) of these mice. The population most affected by nicotine treatment is lymphocytes, ...

Embodiment II

[0353] In vitro studies demonstrating the effect of nicotinic agonists on cytokine expression.

[0354] To further elucidate the mechanisms involved in the inhibitory effect of nicotine on an in vivo model, an alveolar macrophage cell line was used.

[0355] The effect of nicotine or DMPP treatment on TNF-α, IL-10 mRNA expression on AMJ2-C11 cells was tested by RT-PCR. These cytokines are involved in the development of pulmonary inflammatory diseases such as HP, asthma and sarcoidosis (52-55). Nicotine and DMPP treatment showed a significant decrease in TNF mRNA expression (up to 98% decrease in LPS-stimulated cells treated with 40 [mu]M nicotine), but not in a dose-dependent manner. Referring to Figure 3, where results are expressed as % expression, 100% is assigned to the LPS group alone. Band intensities were obtained by dividing the TNF-α band intensity by the β-actin band intensity. Treatment of stimulated cells with different doses (40-160 μM, nicotine and DMPP) induc...

Embodiment III

[0358] In vitro effects of nicotinic agonists on the expression of co-stimulatory molecules.

[0359] The effect of nicotine and DMPP on B7 (CD80) molecule expression was tested in vitro. AMJ2-C11 cells (mouse alveolar macrophages from ATCC) were incubated with 40 μM nicotine or DMPP and stimulated with LPS (0.1 μg / ml) or SR (50 μg / ml) for 48 hours. The percentage of CD80 expression in treated cells was approximately half of that measured in LPS- and SR-stimulated untreated cells. Referring to Figure 8(a), it was shown that nicotine treatment (4 [mu]M, 48 hours) reduced the expression in LPS-stimulated cells to 20%. Referring again to Fig. 8(b), it was shown that DMPP treatment (40 [mu]M, 48 hours) reduced the expression in LPS-stimulated cells to 17% and in SR-stimulated cells to 20%.

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PUM

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Abstract

This invention relates to the use of nicotine receptor agonists or analogs or derivatives thereof for treating inflammatory pulmonary diseases. The invention further relates to pharmaceutical compositions comprising nicotine receptor agonists or analogs or derivatives thereof. Novel compounds of formula wherein R1 ,R2 ,Xa and Ya are as defined herein are also provided.

Description

[0001] Cross References to Related Applications [0002] Continuation-in-Part of Serial No. US10 / 890,987, filed July 15, 2004, which is a continuation-in-part of Serial No. US10 / 469,999, filed February 24, 2004, which was filed March 25, 2002 PCT / CA02 / 00412 national phase application, the entire contents of which are incorporated herein by reference. Background of the invention [0003] a) Field of invention [0004] The present invention relates to methods of treating inflammatory diseases, including various pulmonary diseases, by using or administering nicotinic receptor agonists or analogs and derivatives thereof. [0005] b) Description of prior art [0006] Although a normal man or woman breathes more than one cubic meter of air per hour, our lung defenses can normally deal with the high volumes of particles, antigens, pathogens, gases and smog that are present in the inhaled air. Interaction of these particles with the immune system and other lung defense mechanisms r...

Claims

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Application Information

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IPC IPC(8): C07D223/04A61P29/00A61K31/495A61K31/465A61K31/4439A61K31/439A61K31/221A61K31/551
CPCC07D295/033A61K31/551C07D243/08A61K31/4439A61K31/495A61K31/439C07D241/04A61K31/221A61K31/465C07D401/04C07D295/037A61P11/00A61P11/06A61P11/16A61P29/00A61P35/00A61P37/08C07D451/02C07D453/02
Inventor Y·科尔米耶E·伊斯雷尔-阿萨亚格M-R·布朗谢R·C·焦德鲁特P·拉布里埃
Owner UNIV LAVAL
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