Merz Pharma Gmbh & Co Kgaa

Claudia Jatzke

Ivars Kalvinsh

Wojciech Danysz

Valerjans Kauss

Markus Henrich

Tanja Weil

Christopher Graham Raphael Parsons

Jens Nagel

Aleksandrs Gutcaits

Andrzej Dekundy

Mirko Hechenberger

Juris Fotins

Ronalds Zemribo

Aigars Jirgensons

Karl-Heinz Eisele

Gerd J Mander

Klaus Fink

Maksims Vanejevs

Ieva Jaunzeme

Aleksandra Gutcaits

The present invention provides a method for enhancing the specific uptake of a neurotoxin polypeptide into cells, the method comprising: incubating cells susceptible to neurotoxin intoxication with a neurotoxin polypeptide for a time and under conditions which allow for the neurotoxin polypeptide to exert its biological activity, the incubation comprising at least one of the following steps: (i) K-mediated depolarization of the cells, (ii) a reduced neurotoxin polypeptide exposition time and/or (iii) agitation of the cells during neurotoxin polypeptide exposition, thereby enhancing the specific uptake of the neurotoxin polypeptide into said cells. In addition, the invention pertains to a method for directly determining the biological activity of a neurotoxin polypeptide in cells, comprising: a) incubating cells susceptible to neurotoxin intoxication with a neurotoxin polypeptide for a time and under conditions which allow for the neurotoxin polypeptide to exert its biological activity, the incubation comprising at least one of the following steps: (i) K-mediated depolarization of the cells, (ii) a reduced neurotoxin polypeptide exposition time and/or (iii) agitation of the cells during neurotoxin polypeptide exposition; b) fixing the cells and, optionally, permeabilizing the cells with a detergent; c) contacting the cells with at least a first capture antibody specifically binding to the non-cleaved and neurotoxin-cleaved substrate and with at least a second capture antibody specifically binding to the cleavage site of the neurotoxin-cleaved substrate, under conditions which allow for binding of said capture antibodies to said substrates; d) contacting the cells with at least a first detection antibody specifically binding to the first capture antibody, under conditions which allow for binding of said first detection antibody to said first capture antibody, thus forming first detection complexes and with at least a second detection antibody specifically binding to the second capture antibody, under conditions which allow for binding of said second detection antibody to said second capture antibody, thus forming second detection complexes; e) determining the amount of the first and second detection complexes of step d); and f) calculating the amount of substrate cleaved by said neurotoxin polypeptide in said cells by means of the second detection complexes, thereby determining the biological activity of said neurotoxin polypeptide in said cells.

Methods for enhancing the specific uptake of botulinum neurotoxins into cells

Substituted pyrazolopyrimidine derivatives of formula (I) wherein

Substituted pyrazolo[1,5-A]pyrimidines as metabotropic glutamate receptor modulators

The invention relates to pyrazolopyrimidine derivatives of formula (I) wherein

Substituted pyrazolo[1,5-a]pyrimidines as metabotropic glutamate receptor modulators

The invention relates to ethynyl-substituted tetrahydroquinolinone derivatives as well as their pharmaceutically acceptable salts. The invention further relates to a process for the preparation of such compounds. The compounds of the invention are group I mGluR modulators and are therefore useful for the control and prevention of acute and/or chronic neurological disorders.

Tetrahydroquinolones and their use as modulators of metabotropic glutamate receptors

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Frankfurt am Main, Germany

Claudia Jatzke