TY - JOUR
T1 - Exploratory neuropharmacological evaluation of a conformationally constrained thyrotropin-releasing hormone analogue
AU - Teixidó, Meritxell
AU - Prokai-Tatrai, Katalin
AU - Wang, Xiaoli
AU - Nguyen, Vien
AU - Prokai, Laszlo
N1 - Funding Information:
This work was partially supported by a grant from the National Institutes of Health (MH59380 to L.P.) K.P.-T. is grateful for the seed grant provided by UNTHSC. M.T. was also partially supported by a visiting scholarship from the European Union. L.P. is the Robert A. Welch Professor of the University of North Texas Health Science Center at Fort Worth.
PY - 2007/6/15
Y1 - 2007/6/15
N2 - A conformationally constrained peptidomimetic derived from the endocrine and neuroactive tripeptide thyrotropin-releasing hormone (pGlu-His-Pro-NH2) was synthesized by convenient solid-phase organic chemistry and evaluated as a potential central nervous system agent. While this ethylene-bridged peptide analogue has been reported to lack the hormonal effect of the native peptide, we have shown in animal models that it possesses central nervous system activity characteristic of thyrotropin-releasing hormone. Compared to control, the peptidomimetic showed significant analeptic and antidepressant-like potencies. Moreover, an enhanced selectivity in antidepressant-like effect was measured when compared to that of the native peptide. Immobilized artificial membrane chromatography and in vitro metabolic stability studies also revealed that this constrained peptidomimetic has higher affinity to the blood-brain barrier than the native peptide and is metabolically stable. Consequently, this structure may be used as a template to design centrally selective and metabolically stable thyrotropin-releasing hormone analogues as potential neuropharmaceutical agents.
AB - A conformationally constrained peptidomimetic derived from the endocrine and neuroactive tripeptide thyrotropin-releasing hormone (pGlu-His-Pro-NH2) was synthesized by convenient solid-phase organic chemistry and evaluated as a potential central nervous system agent. While this ethylene-bridged peptide analogue has been reported to lack the hormonal effect of the native peptide, we have shown in animal models that it possesses central nervous system activity characteristic of thyrotropin-releasing hormone. Compared to control, the peptidomimetic showed significant analeptic and antidepressant-like potencies. Moreover, an enhanced selectivity in antidepressant-like effect was measured when compared to that of the native peptide. Immobilized artificial membrane chromatography and in vitro metabolic stability studies also revealed that this constrained peptidomimetic has higher affinity to the blood-brain barrier than the native peptide and is metabolically stable. Consequently, this structure may be used as a template to design centrally selective and metabolically stable thyrotropin-releasing hormone analogues as potential neuropharmaceutical agents.
KW - Analeptic activity
KW - Antidepressant-like activity
KW - Bridged TRH analogue
KW - Immobilized artificial membrane chromatography
KW - Porsolt swim test
KW - Solid-phase organic synthesis
UR - http://www.scopus.com/inward/record.url?scp=34248201148&partnerID=8YFLogxK
U2 - 10.1016/j.brainresbull.2007.02.012
DO - 10.1016/j.brainresbull.2007.02.012
M3 - Article
C2 - 17499643
AN - SCOPUS:34248201148
SN - 0361-9230
VL - 73
SP - 103
EP - 107
JO - Brain Research Bulletin
JF - Brain Research Bulletin
IS - 1-3
ER -