The incorporation of conformationally constrained cyclopropane (2,3- methano-) amino acids into thyrotropin releasing hormone (TRH) will be carried out with a view to stabilizing the peptide to enzymolysis. Conformational studies by NMR spectroscopy will be carried out in order to relate the constrained peptide conformations to the observed bioactivities. Having determined which stereoisomers of the 2,3- methanoamino acids afford bioactive TRH analogs, these isomers will be incorporated into TRH analogs having aliphatic amino acids at the 2- position so that enzymatic degradation of known CNS active compounds will be inhibited. A battery of pharmacological assays will be performed to systematically evaluate the new TRH analogs vis a vis appropriate reference drugs. A complete rationale for structure-activity relationships will be developed and compared with the models proposed for TRH activities.
