Structure-activity relationships of luliberin substituted at position 8.

Substitution of arginine at position 8 of luliberin by the basic amino acids homoarginine, lysine and diaminobutyric acid resulted in analogues in which the luteinizing hormone-releasing activity is markedly reduced, whereas the cross reactivity with specific antibodies to luliberin is preserved. Fluorimetric titrations of these analogues, carried out as with luliberin, revealed pK values of 6.00 +/- 0.05 and of 9.75 +/- 0.15 for His 2 and Try 5 respectively which are essentially the same as in luliberin. However, the rate of collisions between the side chains of His 2 and Trp 3 in these analogues was found to decrease by 36-39%. Substitution at position 8 with the non-basic amino acid omega-nitro arginine yielded an analogue possessing a very low hormonal activity as well as poor recognition of antibodies specific to luliberin. The fluorescence properties of this peptide are markedly different from those of luliberin and its three basic analogues. These results indicate that the functional integrity of the active unit His 2 . . . Tyr 5 . . . Arg 8 in luliberin depends both on size and basicity of the amino acid side chain at position 8.