title: In vitro and in vivo evidence for a lack of interaction with dopamine D2 receptors by the metabotropic glutamate 2/3 receptor agonists 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicaroxylate monohydrate (LY354740) and (-)-2-oxa-4-aminobicyclo[3.1.0] Hexane-4,6-dicarboxylic acid (LY379268).
abstract: Some recently published in vitro studies with two metabotropic glutamate 2/3 receptor (mGluR(2/3)) agonists [(-)-2-oxa-4-aminobicyclo[3.1.0] hexane-4,6-dicarboxylic acid (LY379268) and 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicaroxylate monohydrate (LY354740)] suggest that these compounds may also directly interact with dopamine (DA) D(2) receptors. The current in vitro and in vivo studies were undertaken to further explore this potential interaction with D(2) receptors. LY379268 and LY354740 failed to inhibit D(2) binding in both native striatal tissue homogenates and cloned receptors at concentrations up to 10 microM. LY379268 and LY354740 (up to 10 microM) also failed to stimulate [(35)S]GTPgammaS binding in D(2L)- and D(2S)-expressing clones in the presence of NaCl or N-methyl-d-glucamine. In an in vivo striatal D(2) receptor occupancy assay, LY379268 (3-30 mg/kg) or LY354740 (1-10 mg/kg) failed to displace raclopride (3 microg/kg i.v.), whereas aripiprazole (10-60 mg/kg) showed up to 90% striatal D(2) receptor occupancy. LY379268 (10 mg/kg) and raclopride (3 mg/kg) blocked d-amphetamine and phencyclidine (PCP)-induced hyperactivity in wild-type mice. However, the effects of LY379268 were lost in mGlu(2/3) receptor knockout mice. In DA D(2) receptor-deficient mice, LY379268 but not raclopride blocked both PCP and d-amphetamine-evoked hyperactivity. In the striatum and nucleus accumbens, LY379268 (3 and 10 mg/kg) was without effect on the DA synthesis rate in reserpinized rats and also failed to prevent S-(-)-3-(3-hydroxyphenyl)-N-propylpiperidine-induced reductions in DA synthesis rate. Taken together, the current data fail to show evidence of direct DA D(2) receptor interactions of LY379268 and LY354740 in vitro or in vivo. Instead, these results provide further evidence for a novel antipsychotic mechanism of action for mGluR(2/3) agonists.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. fell_matthew@lilly.com
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fell
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Perry
authors.forename: Julie F
authors.initials: JF
authors.lastname: Falcone
authors.forename: Bryan G
authors.initials: BG
authors.lastname: Johnson
authors.forename: Vanessa N
authors.initials: VN
authors.lastname: Barth
authors.forename: Karen S
authors.initials: KS
authors.lastname: Rash
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Lucaites
authors.forename: Penny G
authors.initials: PG
authors.lastname: Threlkeld
authors.forename: James A
authors.initials: JA
authors.lastname: Monn
authors.forename: David L
authors.initials: DL
authors.lastname: McKinzie
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Marek
authors.forename: Kjell A
authors.initials: KA
authors.lastname: Svensson
authors.forename: David L
authors.initials: DL
authors.lastname: Nelson
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004294:Domperidone / Q000494:pharmacology; D004298:Dopamine / Q000096:biosynthesis; D065127:Dopamine D2 Receptor Antagonists; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D011485:Protein Binding; D020891:Raclopride / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D014162:Transfection
chemical_list: D000596:Amino Acids; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D065127:Dopamine D2 Receptor Antagonists; C118218:LY 379268; D017448:Receptors, Dopamine D2; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D020891:Raclopride; D004294:Domperidone; C104753:eglumetad; D004298:Dopamine