title: JNJ16259685, a highly potent, selective and systemically active mGlu1 receptor antagonist.
abstract: We examined the pharmacological profile of (3,4-dihydro-2H-pyrano[2,3]b quinolin-7-yl) (cis-4-methoxycyclohexyl) methanone (JNJ16259685). At recombinant rat and human metabotropic glutamate (mGlu) 1a receptors, JNJ16259685 non-competitively inhibited glutamate-induced Ca2+ mobilization with IC50 values of 3.24+/-1.00 and 1.21+/-0.53 nM, respectively, while showing a much lower potency at the rat and human mGlu5a receptor. JNJ16259685 inhibited [3H]1-(3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1-ethanone ([3H]R214127) binding to membranes prepared from cells expressing rat mGlu1a receptors with a Ki of 0.34+/-0.20 nM. JNJ16259685 showed no agonist, antagonist or positive allosteric activity toward rat mGlu2, -3, -4 or -6 receptors at concentrations up to 10 microM and did not bind to AMPA or NMDA receptors, or to a battery of other neurotransmitter receptors, ion channels and transporters. In primary cerebellar cultures, JNJ16259685 inhibited glutamate-mediated inositol phosphate production with an IC50 of 1.73+/-0.40 nM. Subcutaneously administered JNJ16259685 exhibited high potencies in occupying central mGlu1 receptors in the rat cerebellum and thalamus ( ED50=0.040 and 0.014 mg/kg, respectively). These data show that JNJ16259685 is a selective mGlu1 receptor antagonist with excellent potencies in inhibiting mGlu1 receptor function and binding and in occupying the mGlu1 receptor after systemic administration.
authors.affiliation: CNS Discovery Research, Johnson and Johnson Pharmaceutical Research and Development, division of Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Lavreysen
authors.forename: Ria
authors.initials: R
authors.lastname: Wouters
authors.forename: François
authors.initials: F
authors.lastname: Bischoff
authors.forename: Sandrina
authors.initials: S
authors.lastname: Nóbrega Pereira
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.forename: Saskia
authors.initials: S
authors.lastname: Blokland
authors.forename: Marijke
authors.initials: M
authors.lastname: Somers
authors.forename: Lieve
authors.initials: L
authors.lastname: Dillen
authors.forename: Anne S J
authors.initials: AS
authors.lastname: Lesage
mesh_terms: D000818:Animals; D001345:Autoradiography; D016466:CHO Cells; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D011714:Pyrans / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000235:genetics; D011994:Recombinant Proteins / Q000187:drug effects; D013762:Tetrahydrofolate Dehydrogenase / Q000172:deficiency; D014162:Transfection
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D007295:Inositol Phosphates; D011714:Pyrans; D011804:Quinolines; D018091:Receptors, AMPA; D011994:Recombinant Proteins; D013762:Tetrahydrofolate Dehydrogenase; C495417:(3,4-dihydro-2H-pyrano(2,3)b-quinolin-7-yl)-(cis-4-methoxycyclohexyl) methanone; C473784:R 214127