Flouret G, Arnold Z S, Majewski T, Petousis N H, Mahan K, Farooqui F, Blum K A, Konopinska D, Natarajan S, Crich D
Department of Physiology, Northwestern University Medical School, Chicago, IL 60611, USA.
J Pept Sci. 1995 Mar-Apr;1(2):89-108. doi: 10.1002/psc.310010202.
We report 104 analogues of the potent antiovulatory antagonist of LHRH, N-Ac-D-Nal-D-Cpa-D-Pal-Ser-Lys(Nic)-D-Lys(Nic)-Leu-Ilys-Pro-D-Ala- NH2, Antide. We replaced the Nic group in Antide with other acyl substituents to modulate size, hydrophilicity or basicity of the molecule, we also replaced the Lys residues with shorter basic amino acids, and made cyclic 5/6 analogues as well as position 5 or 6 dimers. We substituted Ilys8 with other alkyl groups and acyl derivatives. When injected in 0.1% DMSO in water in a typical antiovulatory (AO) assay. Antide gives six rats ovulating out of eight (6/8) at 2 micrograms, 4/8 at 4 micrograms, and in the histamine release assay (HRA). ED50 is > 300 micrograms/ml; [Lys(N-Isobutyl)8]Antide gave 2/8 at 2 micrograms/rat; [Lys (8-Qis)5]Antide gave 1/8 at 1 microgram, and 0/8 at 2 micrograms, and in the HRA ED50. 22 micrograms/ml; [D-Lys(8-Qis)5]Antide gave 4/8 at 1 microgram and 0/8 at 2 micrograms, and in the HRA, ED50 was 27 micrograms/ml; [Lys(8-Qic)8] gave 5/8 at 1 microgram 1/8 at 2 micrograms/ [Lys(2-Pyc)6]Antide gave 3/8 at 1 microgram, and 0/8 at 2 micrograms, and in the HRA ED50 was 116 micrograms/ml; [D-Lys (2-Pyc)5]Antide gave 5/8 at 1 microgram and in the HRA, ED50 was 100- > 300 micrograms/ml; [Lys(2-Pyc)5.D-Lys(2-Pyc)6]Antide gave 2/8 at 1 microgram. The substitutions of the Nic groups of Antide at Lys5 or D-Lys6 with 8-Qis or with 2-Pyc groups seem to give highly potent antiovulatory antagonists of LHRH and constitute significant new leads to generate potent antiovulatory compounds endowed with moderate or low histamine release.
我们报告了促性腺激素释放激素（LHRH）强效抗排卵拮抗剂N-乙酰-D-萘丙氨酸-D-对氯苯丙氨酸-D-对氟苯丙氨酸-丝氨酸-赖氨酸（烟酰胺）-D-赖氨酸（烟酰胺）-亮氨酸-异亮氨酸-脯氨酸-D-丙氨酸-NH2（Antide）的104种类似物。我们用其他酰基取代基替换了Antide中的烟酰胺基团，以调节分子的大小、亲水性或碱性，我们还用较短的碱性氨基酸取代了赖氨酸残基，并制备了环状5/6类似物以及5或6位二聚体。我们用其他烷基和酰基衍生物取代了异亮氨酸8。在典型的抗排卵（AO）试验中，将其注射到含0.1%二甲基亚砜的水中。Antide在2微克时，8只大鼠中有6只排卵（6/8），4微克时4/8排卵；在组胺释放试验（HRA）中，半数有效剂量（ED50）>300微克/毫升；[赖氨酸（N-异丁基）8]Antide在2微克/大鼠时2/8排卵；[赖氨酸（8-Qis）5]Antide在1微克时1/8排卵，2微克时0/8排卵，在HRA中ED50为22微克/毫升；[D-赖氨酸（8-Qis）5]Antide在1微克时4/8排卵，2微克时0/8排卵，在HRA中ED50为27微克/毫升；[赖氨酸（8-Qic）8]在1微克时5/8排卵，2微克/[赖氨酸（2-吡啶基）6]Antide在1微克时3/8排卵，2微克时0/8排卵，在HRA中ED50为116微克/毫升；[D-赖氨酸（2-吡啶基）5]Antide在1微克时5/8排卵，在HRA中ED50为100->300微克/毫升；[赖氨酸（2-吡啶基）5.D-赖氨酸（2-吡啶基）6]Antide在1微克时2/8排卵。用8-Qis或2-吡啶基取代Antide中赖氨酸5或D-赖氨酸6处的烟酰胺基团，似乎能产生强效LHRH抗排卵拮抗剂，并构成了生成具有中度或低度组胺释放的强效抗排卵化合物的重要新线索。
