TY - JOUR
T1 - New analogs of human growth hormone-releasing hormone (1-29) with high and prolonged antagonistic activity
AU - Toth, Katalin
AU - Kovacs, Magdolna
AU - Zarandi, Marta
AU - Halmos, Gabor
AU - Groot, Kate
AU - Nagy, Attila
AU - Kele, Zoltan
AU - Schally, Andrew V.
PY - 1998
Y1 - 1998
N2 - Based on our previous results, in conjunction with various structural considerations, 19 new analogs of the GHRH antagonist [PhAc-Tyr1,D- Arg2,Phe(pCl)6,Abu15,Nle27,Agm29]hGHRH(1-29) (MZ-5-156) were synthesized by the solid-phase method. These compounds were designed to develop further analogs of this class with increased receptor-binding affinity. All analogs had Abu15 and Nle27 modifications and were acylated with phenylacetic acid at the N-terminus. Most of the analogs had D-Arg2 and Phe(pCl)6 substituents and Agm29 or Arg29-NH2 at the C-terminus. Additional single substitutions consisted of the incorporation of D- or L- Tic1, D-Tic2, Tic6 or Phe(pNO2)6 and Arg29-NH2. The Arg29-NH2 analog of MZ-5-156 (KT-48) was further modified by single substitutions using Pal1; D-Tpi2; D- or L-Phe4; Phe(pX)6 X = F, Cl, I; Tyr7; Aib8; Tyr(Me)10 or Phe(pCl)10. Four peptides had multiple substitutions. All the analogs were evaluated for their ability to inhibit GH release induced by hGHRH(1-29)NH2 in vitro and some were also tested in vivo. Peptides [PhAc- Tyr1,D-Arg2,Phe(pI)6,Abu15,Nle27]hGHRH(1-29)NH2 (KT-30), [PhAc- Tyr1,D-Arg2,Phe(pCl)6,Aib8,Abu15,Nle27]hGHRH(1-29)NH2 (KT-50) and [PhAc-Tyr1,D-Arg2,Phe(pCl)6,Tyr(Me)10,Abu15,Nle27]hGHRH(1-29)NH2 (KT-40) with Phe(pI)6, Aib8 or Tyr(Me)10 modifications, respectively, showed high and prolonged inhibitory effect in superfused rat pituitary system. Analog KT-50 also exhibited a strong and long-term inhibitory activity in vivo in rats. Most of the new analogs showed high binding affinities to rat pituitary GHRH receptors.
AB - Based on our previous results, in conjunction with various structural considerations, 19 new analogs of the GHRH antagonist [PhAc-Tyr1,D- Arg2,Phe(pCl)6,Abu15,Nle27,Agm29]hGHRH(1-29) (MZ-5-156) were synthesized by the solid-phase method. These compounds were designed to develop further analogs of this class with increased receptor-binding affinity. All analogs had Abu15 and Nle27 modifications and were acylated with phenylacetic acid at the N-terminus. Most of the analogs had D-Arg2 and Phe(pCl)6 substituents and Agm29 or Arg29-NH2 at the C-terminus. Additional single substitutions consisted of the incorporation of D- or L- Tic1, D-Tic2, Tic6 or Phe(pNO2)6 and Arg29-NH2. The Arg29-NH2 analog of MZ-5-156 (KT-48) was further modified by single substitutions using Pal1; D-Tpi2; D- or L-Phe4; Phe(pX)6 X = F, Cl, I; Tyr7; Aib8; Tyr(Me)10 or Phe(pCl)10. Four peptides had multiple substitutions. All the analogs were evaluated for their ability to inhibit GH release induced by hGHRH(1-29)NH2 in vitro and some were also tested in vivo. Peptides [PhAc- Tyr1,D-Arg2,Phe(pI)6,Abu15,Nle27]hGHRH(1-29)NH2 (KT-30), [PhAc- Tyr1,D-Arg2,Phe(pCl)6,Aib8,Abu15,Nle27]hGHRH(1-29)NH2 (KT-50) and [PhAc-Tyr1,D-Arg2,Phe(pCl)6,Tyr(Me)10,Abu15,Nle27]hGHRH(1-29)NH2 (KT-40) with Phe(pI)6, Aib8 or Tyr(Me)10 modifications, respectively, showed high and prolonged inhibitory effect in superfused rat pituitary system. Analog KT-50 also exhibited a strong and long-term inhibitory activity in vivo in rats. Most of the new analogs showed high binding affinities to rat pituitary GHRH receptors.
KW - Antagonistic activity
KW - GHRH antagonists
KW - GHRH receptor binding
KW - Peptides
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U2 - 10.1111/j.1399-3011.1998.tb00631.x
DO - 10.1111/j.1399-3011.1998.tb00631.x
M3 - Article
C2 - 9516049
AN - SCOPUS:0031913859
VL - 51
SP - 134
EP - 141
JO - Chemical Biology and Drug Design
JF - Chemical Biology and Drug Design
SN - 1747-0277
IS - 2
ER -