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Low molecular weight modulators of the cold menthol receptor trpm8 and use thereof

a low molecular weight, modulator technology, applied in the direction of ketone active ingredients, dental care, organic compounds of group 5/15 elements, etc., can solve the problems of anesthesia

Inactive Publication Date: 2013-09-26
BASF AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent aims to discover new substances that can activate or modulate the TRPM8 receptor, which is a molecule that plays a role in regulating skin, hair, and body temperature. These new substances may be used in a variety of applications, including cosmetics, nutrition, textiles, over-the-counter medication, and packaging.

Problems solved by technology

Elevated menthol concentrations lead to irritation and an anesthetic effect.
However, many of the TRPM8 modulators found hitherto have deficiencies with regard to strength of effect, duration of effect, skin / mucosa irritation, odor, taste, solubility and / or volatility.

Method used

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  • Low molecular weight modulators of the cold menthol receptor trpm8 and use thereof
  • Low molecular weight modulators of the cold menthol receptor trpm8 and use thereof
  • Low molecular weight modulators of the cold menthol receptor trpm8 and use thereof

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

Cloning of Human TRPM8

[0721]The starting point for the cloning of the human TRPM8 receptor is an LnCaP cDNA library. This is, for example, commercially available (e.g. BioChain, Hayward, USA) or can be produced from the androgen-sensitive human prostate adenocarcinoma cell line LnCaP (e.g. ATCC, CRL1740 or ECACC, 89110211) using standard kits.

[0722]The coding TRPM8 sequence (WO 2010 / 026094; and http: / / www.ncbi.nlm.nih.gov / entrez / viewer.fcqi?db=nuccore&id=109689694) can be PCR-amplified and cloned using standard methods. The human TRPM8 gene isolated in this way was used for producing the plasmid pInd_M8, the construction of which is illustrated by the plasmid map according to FIG. 2 of WO 2010 / 026094.

[0723]Alternatively to this, the TRPM8 gene can also be produced synthetically.

reference example 2

Generation of the HEK293 Test Cells

[0724]As test cell system, HEK293 cell line stably transfected with the human TRPM8 DNA (cf. above plasmid pInd-M8) are produced. Preference here is given to HEK293 which offers the option, via the introduced plasmid, of inducing the TRPM8 expression by means of tetracycline.

[0725]Methods for producing suitable test cell systems are known to the person skilled in the art. For example, the details of the preparation of the cells used according to the invention can be found in Behrendt H. J. et al., Br. J. Pharmacol. 141, 2004, 737-745 or the dissertation by Behrendt “Vergleichende funktionale Untersuchungen des Hitze-Capsaicin-Rezeptors (TRPV1) und des Kälte-Menthol-Rezeptors (TRPM8) in rekombinanten und nativen Zellsystemen”. [Comparative functional investigations of the heat capsaicin receptor (TRPV1) and of the cold menthol receptor (TRPM8) in recombinant and native cell systems], accessible from http: / / www-brs.ub.ruhr-uni-bochum.de / netahtml / HSS / ...

reference example 3

Assay on TRPM8 Modulators

[0726]A test comparable with the test already described in the literature by Behrendt H. J. et al., Br. J. Pharmacol. 141, 2004, 737-745 is carried out. The agonization or antagonization of the receptor can be quantified by means of a Ca2+-sensitive dye (e.g. FURA, Fluo-4 etc.). On their own, agonists bring about an increase in the Ca2+ signal; antagonists bring about, in the presence of e.g. menthol, a reduction in the Ca2+ signal (in each case detected via the dye Fluo-4, which has different fluorescent properties as the result of Ca2+).

[0727]Firstly, a fresh culture of transformed HEK cells is prepared in a manner known per se in cell culture flasks. The test cells HEK293-TRPM8 are detached from the cell culture flasks by means of trypsin and 40 000 cells / well are sown out with 100 μl of medium in 96-well plates (Greiner #655948 poly-D-lysine-coated). To induce the receptor TRPM8, tetracycline is added to the growth medium (DMEM / HG, 10% FCS tetracycline-f...

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Abstract

The invention relates to new types of modulators of the cold menthol receptor TRPM8, to methods of modulating the TRPM8 receptor using these modulators; and in particular the use of the modulators for inducing a sensation of coldness; and also the articles and compositions produced using these modulators.

Description

[0001]The invention relates to new types of modulators of the cold menthol receptor TRPM8, methods for modulating the TRPM8 receptor using these modulators; in particular the use of the modulators for inducing a sensation of coldness; and also the articles and compositions produced using these modulators.BACKGROUND OF THE INVENTION[0002]The cold menthol receptor TRPM8 (also referred to as Cold Membrane Receptor (CMR)1) belongs to the family of the “Transient Receptor Potential Ion Channels”, is specifically expressed in a special group of neurons and, in the cell membrane, forms pores (in each case 4 units combine to give a tetramer), which selectively allow Ca2+ ions to pass. The protein has 6 transmembrane domains and a cytoplasmatic C and N terminus. Low temperatures (preferably 10-25° C.) stimulate this receptor, resulting in a signal transduction which is interpreted by the nervous system as a sensation of coldness. The receptor was described for the first time in 2002 as cold ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A23L1/22C07D495/20C07D471/04C07D209/48C07F9/572C07D405/06C07D311/78C07D311/94C07D493/10C07D495/10C07C49/665C07D339/06C07D339/08A61K8/49A61K8/55A61K8/35A61Q19/00C07D491/20A23L27/00
CPCA61K2800/244C07C2103/26C07D491/20C07D495/20C07D471/04C07D209/48C07F9/5728C07D405/06C07D311/78C07D311/94C07D493/10C07D495/10C07C49/665C07D339/06C07D339/08A61K8/49A61K8/4926A61K8/492A61K8/55A61K8/498A61K8/35A61K8/4986A61Q19/00C07J63/008C07C49/675A23L1/22091C07J11/00C07J33/007C07J73/003A23L27/88C07C2603/26A23L27/2056
Inventor SUBKOWSKI, THOMASBOLLSCHWEILER, CLAUSWITTENBERG, JENSSIEGEL, WOLFGANGPELZER, RALF
Owner BASF AG
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