Conformational properties of central nervous system active thyrotropin releasing hormone analogues: probing structure-activity relationships at the molecular level

Crystal structure determinations have been carried out for the following seven thyrotropin releasing hormone analogues: I, (3R,6R)-6-methyl-5-oxothiomorpholin-3-ylcarbonyl-L- histidinyl-L-proline amide; II, (3R,6S)-6-methyl-5-oxothiomorpholin-3-ylcarbonyl-L-histid inyl-L-proline amide; III, (4R)-2-oxothiazolidin-4-ylcarbonyl-D-histidinyl-L-prol ine amide; IV, 5-ethylorotyl-L-histidinyl-L-proline amide; V, 5-n-propylorotyl-L-histidinyl-L-proline amide; VI, 5-bromoorotyl-L-histidinyl-L-proline amide; and VII, Phe2-TRH. A surprising degree of conformational similarity has been observed for the peptide backbone. All peptide bonds are found to be trans. A composite hydrogen-bonding environment has been constructed for the TRH analogue system and examined for its inference with respect to receptor binding. A comparison of the conformations of these analogues with those displayed by Leu5-enkephalin has also been made, and unexpected similarities have been revealed.