A pair of conformationally restricted TRH analogs have been synthesized, Both analogs have the central histidine of TRH replaced by a cyclohexylalanine unit, and both analogs contain a 6,5-bicyclic lactam ring fusing the proline peptide bond into a trans conformation. The analogs differ at the bridgehead stereocenter. The synthesis of the analogs utilized an anodic amide oxidation reaction to selectively functionalize a proline derivative and a titanium tetrachloride-initiated cyclization-rearrangement sequence to assemble the desired bicyclic ring skeleton. The analogs were compared with the unrestricted cyclohexyalanine-containing TRH analog (cyclohexyl-Ala(2)-TRH) in order to determine how the added lactam ring affected the affinity and the potency of the analog for TRH-R. Both the affinity and potency of the restricted analogs were found to be critically dependent on the bridgehead stereochemistry of the bicyclic ring. The analog having R stereochemistry at the bridgehead was 478 times more potent than the S isomer. In addition, the R isomer was found to be approximately 4.7 times more potent than its unrestricted counterpart. Similarly, the R isomer was found to have an affinity for TRH-R that was approximately 3.4 times the affinity of the unrestricted cyclohexyl-Ala(2)-TRH.