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Vol. 305, Issue 2, 608-614, May 2003
Oregon Health and Science University/Oregon National Primate
Research Center, Beaverton, Oregon (J.J., P.M.C.); Merck Research
Laboratories, Rahway, New Jersey (M.G.); Abbott Laboratories, Abbott
Park, Illinois (E.B., J.G.); TAP Pharmaceutical Products, Inc., Lake
Forest, Illinois (D.G.W.)
We expressed a test system of wild-type (WT) rat (r) and human
(h) gonadotropin-releasing hormone (GnRH) receptors (GnRHRs), including
naturally occurring (13) and manufactured (five) "loss-of-function" mutants of the GnRHR. These were used to assess the ability of different GnRH peptidomimetics to rescue defective GnRHR mutants and
determine their effect on the level of membrane expression of the WT
receptors. Among the manufactured mutants were the shortest rGnRHR
C-terminal truncation mutant that resulted in receptor loss-of-function
(des325-327-rGnRHR), two nonfunctional deletion mutants
(des237-241-rGnRHR and des260-265-rGnRHR),
two nonfunctional Cys mutants (C229A-rGnRHR and
C278A-rGnRHR); the naturally occurring mutants included all
13 full-length GnRHR point mutations reported to date that result in
full or partial human hypogonadotropic hypogonadism. The 10 peptidomimetics assessed as potential rescue molecules
("pharmacoperones") are from three differing chemical pedigrees
(indoles, quinolones, and erythromycin-derived macrolides) and were
originally developed as GnRH peptidomimetic antagonists. These
structures were selected for this study because of their predicted
ability to permeate the cell membrane and interact with a defined
affinity with the GnRH receptor. All peptidomimetics studied with an
IC50 value (for hGnRHR) 
2.3 nM had measurable efficacy in
rescuing GnRHR mutants, and within a single chemical class, this
ability correlated to these IC50 values.
Erythromycin-derived macrolides with IC50 values as high as
669.5 nM showed efficacy as rescue compounds. The ability to rescue a
particular receptor was a reasonable predictor of the ability to rescue
others, even across species lines, although particular mutants could
not be rescued by any of the drugs tested.
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