Conformationally restricted TRH analogues: constraining the pyroglutamate region.
A modified synthetic route has been developed so that the steric size of constraints added to the pyroglutamate region of TRH (pGluHisProNH(2)) can be varied. Both an analogue with a smaller ethylene bridge and a larger, more flexible propane bridge in this region have been synthesized. These analogues were synthesized in order to probe why the initial incorporation of an ethane bridge into this region of the molecule had led to an analogue with a binding constant and potency three times lower than that of an directly analogous unconstrained analogue. The data for both analogues indicated that the fall off in activity caused by the ethane bridge in the initial analogue was not caused by the size of the bridge.
Simpson
Jill C
JC
Department of Chemistry, Department of Molecular Biology and Pharmacology, Washington University, St. Louis, MO 63130, USA.
Ho
Chris
C
Shands
E F Berkley
EF
Gershengorn
Marvin C
MC
Marshall
Garland R
GR
Moeller
Kevin D
KD
D001671:Biochemistry / Q000379:methods; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004980:Ethane / Q000737:chemistry; D006801:Humans; D011487:Protein Conformation; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry*; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000737:chemistry*
D018025:Receptors, Thyrotropin-Releasing Hormone; D013973:Thyrotropin-Releasing Hormone; D004980:Ethane; D011761:Pyrrolidonecarboxylic Acid