title: Antinociceptive profile of a selective metabotropic glutamate receptor 1 antagonist YM-230888 in chronic pain rodent models.
abstract: Metabotropic glutamate receptor 1 (mGlu(1) receptor) has been suggested to play an important role in pain transmission. In this study, the effects of a newly-synthesized mGlu(1) receptor antagonist, (R)-N-cycloheptyl-6-({[(tetrahydro-2-furyl)methyl]amino}methyl)thieno[2,3-d]pyrimidin-4-ylamine (YM-230888), were examined in a variety of rodent chronic pain models in order to characterize the potential analgesic profile of mGlu(1) receptor blockade. YM-230888 bound an allosteric site of mGlu(1) receptor with a K(i) value of 13+/-2.5 nM and inhibited mGlu(1)-mediated inositol phosphate production in rat cerebellar granule cells with an IC(50) value of 13+/-2.4 nM. It showed selectivity for mGlu(1) versus mGlu(2)-mGlu(7) subtypes and ionotropic glutamate receptors. YM-230888 recovered mechanical allodynia with an ED(50) value of 8.4 mg/kg p.o. in L5/L6 spinal nerve ligation models. It also showed antinociceptive response at doses of 10 and 30 mg/kg p.o. in streptozotocin-induced hyperalgesia models. In addition, it significantly reduced pain parameters at a dose of 30 mg/kg p.o. in complete Freund's adjuvant-induced arthritic pain models. Although YM-230888 showed no significant effect on rotarod performance time at doses of 10 or 30 mg/kg p.o., it significantly decreased it at a dose of 100 mg/kg p.o. On the other hand, YM-230888 showed no significant sedative effect in locomotor activity measurement up to 100 mg/kg p.o. These results suggest that the blockade of mGlu(1) receptors is an attractive target for analgesics. YM-230888 has potential as a new analgesic agent for the treatment of various chronic pain conditions. In addition, YM-230888 may be a useful tool for the investigation of mGlu(1) receptors.
authors.affiliation: Pharmacology Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba 305-8585, Japan.
authors.forename: Atsuyuki
authors.initials: A
authors.lastname: Kohara
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Nagakura
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kiso
authors.forename: Takashi
authors.initials: T
authors.lastname: Toya
authors.forename: Tomonari
authors.initials: T
authors.lastname: Watabiki
authors.forename: Seiji
authors.initials: S
authors.lastname: Tamura
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Shitaka
authors.forename: Hirotsune
authors.initials: H
authors.lastname: Itahana
authors.forename: Masamichi
authors.initials: M
authors.lastname: Okada
mesh_terms: D000700:Analgesics / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001169:Arthritis, Experimental / Q000503:physiopathology / Q000517:prevention & control; D001562:Benzimidazoles / Q000378:metabolism; D001667:Binding, Competitive; D002460:Cell Line; D002478:Cells, Cultured; D002908:Chronic Disease; D003508:Cycloheptanes / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008026:Ligation / Q000009:adverse effects; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011743:Pyrimidines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013127:Spinal Nerves / Q000601:surgery; D013844:Thiazoles / Q000378:metabolism; D014316:Tritium
chemical_list: C523946:(R)-N-cycloheptyl-6-((((tetrahydro-2-furyl)methyl)amino)methyl)thieno(2,3-d)pyrimidin-4-ylamine; C505455:6-amino-N-cyclohexyl-N,3-dimethylthiazolo(3,2-a)benzimidazole-2-carboxamide; D000700:Analgesics; D001562:Benzimidazoles; D003508:Cycloheptanes; D011743:Pyrimidines; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C104077:metabotropic glutamate receptor type 1; D014316:Tritium