Polyfluoroalkylamine Derivatives of Luteinizing Hormone-Releasing Hormone

A series of C-terminally fluorinated analogs of luteinizing hormone-releasing hormone (LH-RH) was synthesized by a combination of solid-phase and classical techniques and found to have interesting properties when assayed for LH- and FSH-releasing activities over a prolonged period of time in immature male rats. One of the peptides, desGly¹⁰-LH-RH-2,2,2-trifluoroethylamide, was found to be about nine times more effective than LH-RH in releasing LH, or approximately twice as active as the corresponding alkylamide peptide, desGly¹⁰-LH-RH-ethylamide. However, desGly¹⁰-LH-RH-2,2,3,3,3-pentafluoropropylamide was only slightly more active than LH-RH and considerably less active than the corresponding propylamide analog. A family of peptides was also prepared containing D-alanine in position six of the chain in conjunction with the C-terminal modifications. D-Ala⁶,desGly¹⁰-LH-RH-2,2,2-trifluoroethylamide, surprisingly, gave patterns of gonadotropin release which were only as intense and virtually identical with those obtained with D-Ala⁶,desGly¹⁰-LH-RH-ethylamide which in turn releases about 20 times more LH than a similar dose of LH-RH. D-Ala⁶,desGly¹⁰-LH-RH-propylamide also gave almost identical patterns of gonadotropin release. D-Ala⁶,desGly¹⁰,LH-RH-2,2,3,3,3-pentafluoropropylamide was considerably less potent, being only five times more effective than LH-RH.