Structural requirements in positions 1, 2, 3, and 6 of the luteinizing hormone-releasing hormone (LH-RH) for antiovulatory activity.

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.