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Vol. 63, Issue 5, 1082-1093, May 2003
CNS Discovery Research (H.L., X.L., A.S.J.L.) and Departments of
Preclinical Pharmacokinetics (C.J.) and Medicinal Chemistry (F.B.),
Johnson and Johnson Pharmaceutical Research and Development, Beerse,
Belgium; Free University of Amsterdam, Amsterdam, The Netherlands
(H.L., J.E.L.)
R214127 was shown to be a potent and noncompetitive
metabotropic glutamate 1 (mGlu1) receptor-selective antagonist. The
kinetics and pharmacology of
[3H]1-(3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1-ethanone (R214127) binding to rat mGlu1a receptor Chinese hamster ovary (CHO)-dhfr
membranes was investigated, as well as the
distribution of [3H]R214127 binding in rat brain tissue
and sections. Specific binding to rat mGlu1a receptor
CHO-dhfr membranes was ~92% of total and was optimal
at 4°C. Full association was reached within 5 min, and
[3H]R214127 bound to a single binding site with an
apparent KD of 0.90 ± 0.14 nM and a
Bmax of 6512 ± 1501 fmol/mg of
protein. Inhibition experiments showed that [3H]R214127
binding was completely blocked by
2-quinoxaline-carboxamide-N-adamantan-1-yl (NPS 2390),
(3aS,6aS)-6a-naphtalan-2-ylmethyl-5-methyliden-hexahydro-cyclopenta[c]furan-1-on (BAY 36-7620), and
7-(hydroxyimino)cyclo-propa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt), but was not displaced by competitive mGlu1 receptor ligands such as glutamate and quisqualate, suggesting that
R214127, NPS 2390, BAY 36-7620, and CPCCOEt bind to the same site or
mutually exclusive sites. Experiments using rat cortex, striatum,
hippocampus and cerebellum revealed that [3H]R214127
labeled a single high-affinity binding site
(KD ~ 1 nM).
Bmax values were highest in the cerebellum
(4302 ± 2042 fmol/mg of protein) and were 741 ± 48, 688 ± 125, and 471 ± 68 fmol/mg of protein in the striatum,
hippocampus, and cortex, respectively. The distribution of
[3H]R214127 binding in rat brain was investigated in more
detail by radioligand autoradiography. A high density of binding sites was detected in the molecular layer of the cerebellum. Moderate labeling was seen in the CA3 and dentate gyrus of the hippocampus, thalamus, olfactory tubercle, amygdala, and substantia nigra
reticulata. The cerebral cortex, caudate putamen, ventral pallidum, and
nucleus accumbens showed lower labeling. The high affinity and
selectivity of [3H]R214127 for mGlu1 receptors renders
this compound the ligand of choice to study the native mGlu1 receptor
in brain.
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