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Vol. 288, Issue 2, 827-833, February 1999
Departments of
Pharmacology (A.E.R., M.J.C., J.H.W., F.M.),
Biological Chemistry (F.M.),
Psychology (J.H.W.), and
Mental Health
Research Institute (A.M., H.A.) University of Michigan, Ann Arbor,
Michigan
A C6 glioma cell line stably transfected with the human
kappa opioid receptor (
OR) was used to characterize
receptor binding and G protein activation via the OR by a
comprehensive series of opioid ligands. The ligand-binding affinity for
[3H]5
,7,8
(-)-N-methyl-N-(7-Cl-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl)benzene acetamide (U69593) was similar to that observed in monkey brain membranes and was 10-fold lower in the presence of sodium and GDP. Both
peptide and nonpeptide agonists maximally stimulated [35S]GTP
S binding. The stimulation of
[35S]GTPS binding was blocked by pretreatment of cells
with pertussis toxin. Partial stimulation of [35S]GTPS
binding via the OR was observed for several ligands that are
antagonists at the mu opioid receptor, suggesting an
additional mechanism of drug action. The ability of isomers of
tifluadom and levallorphan to stimulate [35S]GTPS
binding indicates that the chiral carbon of levallorphan, a
benzomorphan derivative, imparts a greater degree of stereoselectivity than does the chiral carbon in the benzodiazepine derivative tifluadom. In addition, (
)tifluadom, the less potent isomer of tifluadom, which
is also a -aminobutyric acidA receptor agonist,
stimulated [35S]GTPS binding. In contrast,
d-pentazocine, (+)SKF10047, (+)cyclazocine, and
d-ethylketocyclazocine displayed no agonist
activity. OR-selective antagonist norbinaltorphimine
competitively inhibited the stimulation of [35S]GTPS
binding by the active isomers of ethylketocyclazocine, cyclazocine, and
nalorphine to the same degree, indicating that all three ligands are
eliciting an effect via the OR. The results suggest that these cells
express a homogeneous population of OR, and that their
[35S]GTPS-binding properties make them an excellent
means to assess OR efficacy.
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