Brain concentrations of mGluR5 negative allosteric modulator MTEP in relation to receptor occupancy--Comparison to MPEP.
BACKGROUND
To verify relation between brain free levels, receptor occupancy in vivo and in vitro affinity at the target for mGluR5 negative allosteric modulator (NAM) MTEP.


METHODS
We evaluated plasma and brain extra-cellular fluid (ECF) concentration of MTEP at behaviourally active dose (5mg/kg) using in vivo microdialysis. These values were compared it to the affinity in vitro (receptor binding and FLIPR) and to receptor occupancy in vivo. Another, related substance, MPEP was used for comparison.


RESULTS
MTEP and MPEP respectively inhibited mGluR5 receptors function in vitro with an affinity of 25.4 and 12.3 nM respectively. Accordingly peak ECF (extracellular fluid) levels were 1.3 and 0.14 μM, and peak total plasma levels were 7-11 and 2.6 μM. The ED50 for in vivo receptor occupancy was for both agents in the range of 0.8-0.7 mg/kg.


CONCLUSIONS
At behaviourally active dose MTEP produced complete mGluR5 receptor occupancy but over 50 times higher ECF concentrations than affinity for mGluR5 receptor in vitro. This difference is seems lower for other mGluR5 NAM compounds such as MPEP. A possibly explanation could be different distribution in body compartments of both agents leading to errors of estimation with the microdialysis technique or different pharmacological activity at the receptor.
Merz Pharmaceuticals GmbH, Frankfurt/Main, Germany.
Jens
J
Nagel
Merz Pharmaceuticals GmbH, Frankfurt/Main, Germany.
Sergio
S
Greco
Merz Pharmaceuticals GmbH, Frankfurt/Main, Germany.
Chris G
CG
Parsons
Brains On-Line B.V., Groningen, The Netherlands.
Gunnar
G
Flik
rent-a-lab, Reutlingen, Germany.
Carsten
C
Tober
Merz Pharmaceuticals GmbH, Frankfurt/Main, Germany.
Kai-Uwe
KU
Klein
Merz Pharmaceuticals GmbH, Frankfurt/Main, Germany. Electronic address: wojciech.danysz@merz.de.
Wojciech
W
Danysz
D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D008297:Male; D011485:Protein Binding / Q000502:physiology; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013844:Thiazoles / Q000378:metabolism* / Q000494:pharmacology
C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D013844:Thiazoles; C121465:6-methyl-2-(phenylethynyl)pyridine
Affinity; Brain PK; Brain microdialysis; Plasma; mGluR5 NAMs