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Vol. 298, Issue 2, 812-819, August 2001
F. Hoffmann-La Roche AG, Pharma Division, Preclinical Research,
Basel, Switzerland
The novel nonpeptide orphanin FQ/nociceptin (OFQ/N) ligand
{(1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one} (Ro 64-6198) was characterized in vitro and in vivo for its
agonistic potential. Ro 64-6198 was 130- to 3500-fold selective for the OFQ/N receptor (ORL1) compared with opiate receptors. In the cAMP inhibition assay, Ro 64-6198 was a full agonist at the ORL1 and a
partial agonist at the mu opiate receptor. When human embryonic kidney
293 cells stably expressing the human ORL1 receptor were pre-exposed
(30 min) to either OFQ/N or Ro 64-6198, the ability of both agonists to
inhibit forskolin-mediated cAMP accumulation was strongly reduced,
indicating a functional desensitization of the second messenger
cascade. However, acidic washes of OFQ/N-exposed cells fully restored
the sensitivity of the ORL1 receptor for agonists. In contrast, the
cAMP response in Ro 64-6198-exposed cells remained impaired after
acidic washes, suggesting sustained receptor internalization at 30 min.
In agreement with this finding, the number of cell-surface ORL1
receptors was significantly reduced after Ro 64-6198 pre-exposure, and
this effect could be blocked with high sucrose concentrations. When Ro
64-6198 was chronically administered to rats, no signs of tolerance to
its anxiolytic-like effects were detected following 15 days of daily
drug exposure. In agreement with the behavioral results, Ro 64-6198 was
able to reduce brain ORL1 binding sites in both acutely and chronically treated rats. Full recovery of ORL1 binding sites was observed 24 h after Ro 64-6198 administration with a
t1/2 of ~5.5 h. These data show that
nonpeptide agonists at the ORL1 receptor have a good clinical potential
as anxiolytics without causing tolerance.
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