ISSN:
1573-6903
Keywords:
Thyrotropin-releasing hormone
;
TRH receptor
;
TRH analogs
;
CG3509
;
CG3703
;
RX77368
;
MK-771
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract [3H](3-Me-His2) thyrotropin-releasing hormone ([3H]MeTRH) bound to TRH receptors in rodent, rabbit and dog brain and spinal cord (SC), and in rat, sheep, bovine and dog anterior pituitary (PIT) glands, with high affinity (dissociation constants, Kds=5–9 nM; n=3–4) but to different densities of these sites (B max range 6–145 fmol/mg protein) (rabbit SC〉sheep PIT≫G.pig brain〉dog brain〉rat brain〉bovine and dog PIT). Various TRH analogs competitively inhibited [3H]MeTRH binding in these tissues with a similar rank order of potency: MeTRH〉TRH〉 CG3703≥RX77368≥MK-771〉TRH Glycinamide〉Glu1-TRH≫CG3509≥NVal2-TRH〉〉〉TRH free acid〉〉〉and cyclo-His-Pro, indicating a pharmacological similarity of CNS and pituitary TRH receptors. While most TRH analogs displaced [3H]MeTRH binding with a similar potency in the different species, TRH exhibited a 2-fold lower affinity in the rat and G.pig brain than in other tissues of other species. Similarly, CG3703 was 2.4–4.5 times more active in the rabbit brain than in the rodent and dog brain, and also more potent in the rabbit brain as compared to the sheep PIT. However, MK-771 and RX77368 had a similar affinity for the brain TRH receptors in the different species but RX77368 was 2-fold more active in the SC preparations and ≈3–4-fold less active in the sheep PIT when compared to the brain homogenates. RX 77368 exhibited the highest affinity for the dog PIT TRH receptor. In contrast, MK-771 showed a similar affinity for the brain, SC and PIT TRH receptor apart from in the rat PIT where it had the highest affinity. Similarly, TRH glycinamide was more active in the dog brain than rodent and rabbit brain. These data suggest that while the rank order of potency of TRH analogs is similar in the species examined, certain analogs appear to be more potent in certain tissues of some species than in others. In addition, the current results have shown that CG3703 is almost equipotent with RX77368 and MK-771 in most species but is substantially more active than its related analog, CG3509 in the brain, SC and PIT. Taken together, these observations may have some relevance to the future clinical applications of these metabolically stabilized TRH analogs.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00965695
Permalink
