The effect of increased hydrophobicity at position 6 of luteinizing hormone-releasing hormone (LH-RH) has been investigated by the incorporation of a series of 15 very hydrophobic, unnatural D-amino acids at this position. The unnatural amino acids studied can be considered analogues of phenylalanine with carbocyclic aromatic side chains consisting of substituted phenyl (eg, 2, 4, 6-trimethylphenyl, p-biphenyl) or polycyclic aromatic (eg, naphthalene, anthracene) units. When enzymatic resolution (subtilisin Carlsberg) of the most hydrophobic aminoacids failed, the racemic amino acids were incorporated, and the diastereomeric LH-RH analogues were resolved by preparative high-performance liquid chromatography. The analogues were synthesized by the solid-phase technique. All of the synthetic compounds were very potent LH-RH superagonists, but [6-(3-(2-naphthyl)-D-alanine)] LH-RH,[6-(3-(2-naphthyl)-D-alanine), 7-(jV"-methylleucine)] LH-RH and [6-(3-(2, 4, 6-trimethylphenyl)-D-alanine)} LH-RH appear to be among the most potent LH-RH agonist analogues yet reported when tested in a rat estrus cyclicity suppression assay designedto show the paradoxical antifertility effects of these compounds [ED60~ 7 X 10~ 8 g; twice daily in saline]. These analogues are twice as potent as [D-Trp6, ProNHEt9] LH-RH in this assay system (ie,~ 200 times the potency of LH-RH).

The isolation and determination of the structure of lu-teinizing hormone-releasing hormone (< Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2, LH-RH) from porcine2 and ovine3 45hypothalami have led to the synthesis of a large series of analogues, 4, 5 some of which have exhibited dra-matically enhanced agonist (“superagonist”) or antagonist potency. With further pharmacological study it has be-come clear that such compounds offer promising routes to thecontrol of reproduction in both males and females. Of particular interestto us has been the demonstration that chronic treatment with pharmacological doses of long lived superagonist LH-RH analogues leads to “paradoxical” antifertility6 and antisteroidal7 effects which appear to be due tothe desensitization of target cells in the anterior pituitary8 and the gonads. 9 These results and their implications for fertility control led us to undertake a syn-thetic programdesigned to yield more potent superagonist LH-RH analogues with a better pharmacodynamic profile. Previous analogue programs have demonstrated that the primary sites for successful modification of the LH-RH structure to yield superagonist analogues are at positions 6, 7, and 10. At position 6, D-amino acids led to major increases (3-40 times) in potency, 10 with an apparent preference for lipophilic amino acids. D-Trp gave the most