Humphries J, Wan Y P, Wasiak T, Folkers K, Bowers C Y
J Med Chem. 1979 Jul;22(7):774-7. doi: 10.1021/jm00193a005.
Sixteen analogues of the luteinizing hormone-releasing hormone (LH-RH) were synthesized by the solid-phase method. In new and surprising relationships, it was found that the substitution of D-Trp into position 3 of [D- less than Glu1,D-Phe2,amino acid3,D-Phe6]-LH-RH significantly enhanced the antiovulatory potency, but substitution by Pro, N-Me-Phe,N-Me-Leu, or L-Trp reduced antiovulatory activity. The substitution of L- less than Glu in position 1 of [D-Phe2,Pro3,D-Phe6]-LH-RH by cyclohexylcarbonyl (Chc), benzoyl (Bz), Ac, Hyp, Ac-Met, hydrogen, Pro, and D- less than Glu residues, and the substitution of D-Phe in position 2 by D-Trp, D-His, D-Phg, and L-Phe residues resulted in analogues with no antiovulatory activity at 750 microgram/rat. Structural requirements for the design of inhibitors of higher potency have been discussed.
采用固相法合成了16种促黄体生成激素释放激素（LH-RH）类似物。研究发现，在[D-小于Glu1，D-Phe2，氨基酸3，D-Phe6]-LH-RH的第3位用D-Trp取代，以一种新的、令人惊讶的关系显著增强了抗排卵效力，但用Pro、N-Me-Phe、N-Me-Leu或L-Trp取代则降低了抗排卵活性。在[D-Phe2，Pro3，D-Phe6]-LH-RH的第1位用环己基羰基（Chc）、苯甲酰基（Bz）、乙酰基（Ac）、Hyp、Ac-Met、氢、Pro和D-小于Glu残基取代L-小于Glu，以及在第2位用D-Trp、D-His、D-Phg和L-Phe残基取代D-Phe，得到的类似物在750微克/大鼠时无抗排卵活性。文中讨论了设计高效抑制剂的结构要求。
