Syntheses and biological evaluation of analogs of luteinizing hormone-releasing hormone (LH-RH) modified in position 2, 3, 4 or 5

Syntheses by the conventional methods as well as the chemical, physical and biological properties are described of the following analogs of the LH-releasing hormone (LH-RH): Leu³]-LH-RH, Phe³]-LH-RH, Trp²] His³]-LH-RH, Des-Trp³-LH-RH, Des-His²-Phe⁵]-LH-RH, Ala⁴]-LH-RH, Phe⁵]-LH-RH and Ala⁴] Phe⁵]-LH-RH. $\text{In vivo}$ assays showed that Leu³]-LH-RH did not release LH in doses as high as 5 – 25 μg, having less than 0.0008% of LH-RH activity, while Phe³]-LH-RH had 0.43% of the LH-RH activity of natural LH-RH. The LH-RH activities of Trp²] His³]-LH-RH, Des-Trp³-LH-RH and Des-His²-Phe⁵]-LH-RH were extremely low. On the other hand, Ala⁴]-LH-RH, Phe⁵]-LH-RH and Ala⁴] Phe⁵]-LH-RH had significant LH-RH activity. The structure-activity relationship of LH-RH is discussed on the basis of these findings.