New antagonists of LHRH II. Inhibition and potentiation of LHRH by closely related analogues

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Abstract
Modifications of the previously described LHRH antagonists, [Ac-d-Nal(2)1, d-Phe(4Cl)2, d-Trp3, d-Cit6, d-Ala10]LHRH and the corresponding d-Hci6 analogue, have been made to alter the hydrophobicity of the N-terminal acetyl-tripeptide portion. Substitution of d-Trp3 with the less hydrophobic d-Pal(3) had only marginal effects on the antagonistic activities and receptor binding potencies of the d-Cit/d-Hci6 analogues, but it appeared to further improve the toxicity lowering effect of d-Cit/d-Hci6 substitution. Antagonists containing d-Pal(3)3 and d-Cit/d-Hci6 residues, i.e. [Ac-d-Nal(2)1, d-Phe(4Cl)2, d-Pal(3)3d-Cit6, d-Ala10]LHRH (SB-75) and [Ac-d-Nal(2)1, d-Phe(4Cl)2, d-Pal(3)3, d-Hci6, d-Ala10]LHRH (SB-88), were completely free of the toxic effects, such as cyanosis and respiratory depression leading to death, which have been observed in rats with the d-Trp3, d-Arg6 antagonist and related antagonists. Replacement of the N-acetyl group with the hydrophilic carbamoyl group caused a slight decrease in antagonistic activities, particularly in vitro. Introduction of urethane type acyl group such as methoxycarbonyl (Moc) or t-butoxycarbonyl (Boc) led to analogues that showed LHRH-potentiating effect. The increase in potency induced by these analogues, e.g. [Moc-d-Nal(2)1, d-Phe(4Cl)2, d-Trp3, d-Cit6, d-Ala10]LHRH and [Boc-d-Phe1, d-Phe(4Cl)2, d-Pal(3)3, d-Cit6, d-Ala10]LHRH, was 170-260% and persisted for more than 2 h when studied in a superfused rat pituitary system.