Ethanol solutions were prepared by diluting 190 proof ethanol (Decon Labs, Inc., King of Prussia, PA) in filtered water (for drinking experiments) or phosphate buffered saline (PBS, for injections). LY466195 was provided by Eli Lilly & Co., Indianapolis, IN, USA (for in vitro and in vivo characterization, see Weiss et al., 2006 (link)).
Briefly, LY466195 is a decahydroisoquinoline ((3S,4aR,6S,8aR)-6-[[(2S)-2-carboxy-4,4-difluoro-1-pyrrolidinyl]-methyl]decahydro-3-isoquinolinecarboxylic acid) shown to act as a selective GluK1*KAR competitive antagonist (Ki = 52±22 nM measured by displacement of [3H]kainate from human recombinant kainate receptors expressed on HEK293 cells), with no measurable affinity for adrenergic, dopaminergic, serotonergic, histaminergic and muscarinic receptors (Weiss et al., 2006 (link)). Pharmacokinetic studies in adult rats treated with the LY466196 prodrug ester (30 mg/kg, per os) showed a half-life in plasma of 48 min and approximately 40% bioavailability. Although no data exists on LY466195’s brain bioavailability following systemic administration, other decahydroisoquinolines (i.e., LY293558) have been shown to readily cross the blood-brain barrier in rats (Apland et al., 2013 (link)).
LY466195 solutions were prepared by dissolving LY466195 in PBS. Chemicals used for in vivo microdialysis were from Sigma-Aldrich (Millipore Sigma, St. Louis, MO).
Briefly, LY466195 is a decahydroisoquinoline ((3S,4aR,6S,8aR)-6-[[(2S)-2-carboxy-4,4-difluoro-1-pyrrolidinyl]-methyl]decahydro-3-isoquinolinecarboxylic acid) shown to act as a selective GluK1*KAR competitive antagonist (Ki = 52±22 nM measured by displacement of [3H]kainate from human recombinant kainate receptors expressed on HEK293 cells), with no measurable affinity for adrenergic, dopaminergic, serotonergic, histaminergic and muscarinic receptors (Weiss et al., 2006 (link)). Pharmacokinetic studies in adult rats treated with the LY466196 prodrug ester (30 mg/kg, per os) showed a half-life in plasma of 48 min and approximately 40% bioavailability. Although no data exists on LY466195’s brain bioavailability following systemic administration, other decahydroisoquinolines (i.e., LY293558) have been shown to readily cross the blood-brain barrier in rats (Apland et al., 2013 (link)).
LY466195 solutions were prepared by dissolving LY466195 in PBS. Chemicals used for in vivo microdialysis were from Sigma-Aldrich (Millipore Sigma, St. Louis, MO).