NON-COMPETITIVE METABOTROPIC GLUTAMATE 1 RECEPTOR ANTAGONISTS BLOCK ACTIVITY OF SLOWLY ADAPTING TYPE I MECHANORECEPTOR UNITS IN THE RAT SINUS HAIR FOLLICLE

Previous studies suggested that Group I metabotropic glutamate (mGlu) receptors play a role in mechano-transduction processes of slowly adapting type I mechanoreceptors. Using an isolated rat sinus hair follicle preparation we tested a range of compounds. Surprisingly, only non-competitive mGlu1 receptor antagonists produced profound and long-lasting depression of mechanically evoked firing. 6-Amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-alpha]benzimidazole-2- carboxamide hydrochloride (YM-298198) had an IC50 of 8.7 mu M (95% CI 5.7 to 13.2 mu M), representing the most potent known blocker of type I mechanoreceptors. The derivative 6-amino-N-cyclohexyl-3-methylthiazolo[3,2-alpha]benzimidazole-2-carboxamide hydrochloride (desmethyl YM-298198) had a comparable potency. Another compound 7-(hydroxyimino)cyclopropa[b]chromen-la-carboxylate ethyl ester (CPCCOEt) had a similar depressant effect, although it was less potent with an approximate IC50 of 100 mu M. Between three and seven times the concentration of CPCCOEt and YM-298198 respectively was required to produce similar depressions in slowly adapting type 11 units. No depression, and some weak excitatory effects, were observed using the following ligands: the competitive mGlu1 receptor antagonist alpha-amino-5-carboxy-3-methyl-2-thiopheneacetic acid (3-MATIDA) (300 mu M), the phosphoserine phosphatase inhibitor DL-2-amino-3-phosphonoproplonic acid (DL-AP3) (2 mM), non-competitive mGlu5 receptor antagonists 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; (S)-3,5-DHPG, (S)-3,5-dihydroxyphenylglycine (MTEP) (10 mu M) and 2-methyl-6(phenylethynyl)pyridine hydrochloride (MPEP) (100 mu M), the mGlu1 receptor agonist (S)-3,5-dihydroxyphenylglycine ((S)3,5-DHPG) (500 mu M), and the mGlu5 receptor agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) (11 mM). The results suggest that the non-competitive mGlu1 receptor antagonists are not acting at conventional mGlu1 receptors but at other binding sites, possibly those directly associated with mechanogated channels or on any of a number of indirect biochemical pathways. YM-298198 and related compounds may prove to be useful ligands to identify mechanosensitive channel proteins. The selective interference of type I units may provide further evidence that Merkel cells are mechanotransducers. Finally such compounds may deliver insights or treatments for Merkel cell carcinoma. Crown Copyright (c) 2009 Published by Elsevier Ltd on behalf of IBRO. All rights reserved.