SYNTHETIC PEPTIDES HAVING PITUITARY GROWTH HORMONE RELEASING ACTIVITY

摘要

Novel peptides having the amino acid sequence selected from a group consisting of wherein X1, X2; and X3 are selected from a group consisting of N-terminal and desamino alpha-carbon substitutions and a and b are 0 or 1, provided that a and b are always 0 when A1 is a desamino residue; A1 and A4 are selected from a group consisting of histidyl, arginyl, lysyl alpha -naphthylalanyl, beta -naphthylalanyl, isoquinolyl, tyrosyl, tryptophyl, phenylaanyl, homologues and analogues thereof, and, with respect to A1 only the desamino forms thereof; A2 and A5 are selected from a group consisting of D-histidyl, D-arginyl, D-lysyl, D- alpha -naphthylalanyl, D- beta -naphthylalanyl, D-isoquinolyl, D-tyrosyl, D-tryptophyl, D-phenylalanyl, homologues and analogues thereof, and, with respect to A5 only, the descarboxy forms thereof; A3 is selected from a group consisting of glycyl, alanyl, valyl, leucyl, isoleucyl, prolyl, seryl, threonyl, methionyl, aspartyl, glutamyl, asparginyl, glutaminyl, histidyl, D-alanyl, D-valyl, D-leucyl, D-isoleucyl, D-prolyl, D-seryl, D-threonyl, D-methionyl, D-aspartyl, D-glutamyl, D-asparaginyl, D-glutaminyl, D-histidyl, and homologues and analogues thereof; A6 is selected from a group consisting of amino acid residues of the L- and D- configuration, homologues and analogues thereof, and the descarboxy forms thereof; and Y is selected from a group consisting of C-terminal and descarboxy alpha-carbon substitutions; and the pharmaceutically acceptable salts thereof; provided that (a) when (1) a is 1 and b is 0 and X1 and X2 are selected from the group consisting of tyrosyl, tryptophyl and phenylalanyl; (3) A3 is selected from the group consisting of glycyl, alanyl, valyl, leucyl, isoleucyl, prolyl, seryl, threonyl, methionyl, aspartyl, glutamyl, asparaginyl, glutaminyl, and histidyl; and (4) Y is selected from the group consisting of -NR1R2, -OR, and -CH2OR, wherein R, R1 and R2 are selcted from a group consisting of hydrogen and straight and branched chain alkyl groups containing 1-6 carbon atoms, then at least one of A2 and A5 is selected such that it is not from a group consisting of D-tyrosyl, D-tryptophyl, D-phenylalanyl, and, with respect to A5, the descarboxy forms thereof; (b) when (1) a is 1 and b is 0 and X1 and X2 are selected from the group consisting of -H and -CH3; (2) A2 and A5 are selected from the group consisting of D-tyrosyl, D-tryptophyl, D-phenylalanyl, and, with respect to A5, the descarboxy forms thereof; (3) A3 is seleceted from the group consisting of glycyl, alanyl, valyl, leucyl, isoleucyl, prolyl, seryl, threonyl, methionyl, aspartyl, glutamyl, asparaginyl, glutaminyl and histidyl; and (4) Y is selected from a group consisting of -NR1R2, -OR, and -CH2OR, wherein R, R1, and R2 are selected from a group consisting of hydrogen and straight and branched chain alkyl groups containing 1-6 carbon atoms; then at least on of A1 and A4 is selected such that is not from a group consisting of tyrosyl, tryptophyl, and phenylalanyl; (c) when (1) a is 1 and b is 0 and X min 1 and X min 2 are selected from the group consisting of -H, -CH3, and -CHOCH3; (2) A1 and A4 are selected from the group consisting of tyrosyl, tryptophyl, and phenylalanyl; (3) A3 is selected from the group consisting of glycyl, alanyl, valyl, leucyl, isoleucyl, seryl, threonyl, methionyl, asparaginyl, and glutaminyl; (4) A6 is selected from the group consisting of asparaginyl, glutaminyl, glutamyl, arginyl, lysyl, seryl, threonyl, and the descarboxy forms thereof; and (5) Y is selected from the group consisting of -NR1R2, -OR, and -CH2OR, wherein R, R1, and R2 are selected from a group consisting of hydrogen and straight and branched chain alkyl groups containing 1-6 carbon atoms; then at least one of A2 and A5 is selected such that it is not from a group consisting of D-tyrosyl, D-tryptophyl, and D-phenylalanyl; and (d) when (1) a is 1 and b is 0 and X min 1 and X min 2 are selected from the group consisting of -H, PCH3, and -CHOCH3; (2) A2 and A5 are selected from the group consisting of D-tyrosyl, D-tryptophyl, and D-phenylalanyl; (3) A3 is selected from the group consisting of glycyl, alanyl, valyl, leucyl, isoleucyl, seryl, threonyl, methionyl, asparaginyl, and glutaminyl; (4) A6 is selected from the group consisting of asparaginyl, glutaminyl, glutamyl, arginyl, lysyl, seryl, threonyl, and the descarboxy forms thereof; and (5) Y is selected from the group consisting of -NR1R2, -OR, and -CH2OR, wherein R, R1, and R2 are selected from a group consisting of hydrogen and straight and branched chain alkyl groups containing 1-6 carbon atoms; then at least one of A1 and A4 is selected such that is not from a group consisting of tyrosyl, tryptophyl, and phenyl. In addition, this invention encompsasses a combination of compounds comprising (a) at least one peptide having the formula III wherein X sec 1, X sec 2, and X sec 3 are selected from a group consisting of N-terminal and desamino alpha-carbon substitutions; a and b are 0 or 1, provided that a and b are always 0 when A1 is a desamino residue; A1 and A4 are selected from a group consisting of histidyl, arginyl, lysyl, alpha -naphthylanalyl, beta -naphthylalanyl, isoquinolyl, tyrosyl, tryptophyl, phenylalanyl, homologues and analogues thereof, and, with respect to A1 only, the desamino forms thereof; A2 and A5 are selected from a group consisting of D-histidyl, D-arginyl, D-lysyl, D- alpha -napthylalanyl, D-tryptophyl, D- beta -naphthylalanyl, D-isoquinolyl, D-tyrosyl, D-tryptophyl, D-phenylalanyl homologues and analogues thereof, and with respect to A5 only, the descrboxy forms thereof; A3 is selected from a group consisting of glycyl, alanyl, valyl, leucyl, isoleucyl, prolyl, seryl, threonyl, methionyl, aspartyl, glutamyl, asparaginyl, glutaminyl, histidyl, D-alanyl, D-valyl, D-leucyl, D-isoleucyl, D-prolyl, D-seryl, D-threonyl, D-methionyl, D-aspartyl, D-glutamyl, D-asparaginyl, D-glutaminyl, D-hystidyl, and homologues and analogues thereof; A6 is selected from a group consisting of amino acid residues of the L- and D-configuration, homologues and analogues thereof, and the descarboxy forms thereof; and Y is selected from a group consisting of C-terminal and descarboxy alpha-carbon substitutions; and the pharmaceutically acceptable salts thereof; and (b) at least one growth promoting agent. Combinations comprising at least one of the above-described peptides and at least one growth promoting agent. These peptides and combinations act directly on the pituitary to release growth hormone therefrom.