Conformational properties of central nervous system active thyrotropin releasing hormone analogs: probing structure-activity relationships at the molecular level
Crystal structure determinations were carried out for the following 7 TRH analogs: (3R,6R)-6-methyl-5-oxothiomorpholin-3-ylcarbonyl-L-histidinyl-L-prolinamide; (3R,6S)-6-methyl-5-oxothiomorpholin-3-ylcarbonyl-L-histidinyl-L-prolinamide; (4R)-2-oxothiazolidin-4-ylcarbonyl-D-histidinyl-L-prolinamide; 5-ethylorotyl-L-histidinyl-L-prolinamide; 5-n-propylorotyl-L-histidinyl-L-prolinamide; 5-bromoorotyl-L-histidinyl-L-prolinamide; and Phe2-TRH. A surpising degree of conformational similarity was observed for the petpide backbone. All peptide bonds with trans. A composite hydrogen-bonding environment was constructed for the TRH analog system and examined for its inference with respect to receptor binding. A comparison of the conformations of these analogs with those displayed by Leu5-enkephalin was made, and unexpected similarities were revealed.