title: New analogs of human growth hormone-releasing hormone (1-29) with high and prolonged antagonistic activity.
abstract: 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(1-2 9)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]h GHRH(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.
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70146, USA.
authors.forename: K
authors.initials: K
authors.lastname: Toth
authors.forename: M
authors.initials: M
authors.lastname: Kovacs
authors.forename: M
authors.initials: M
authors.lastname: Zarandi
authors.forename: G
authors.initials: G
authors.lastname: Halmos
authors.forename: K
authors.initials: K
authors.lastname: Groot
authors.forename: A
authors.initials: A
authors.lastname: Nagy
authors.forename: Z
authors.initials: Z
authors.lastname: Kele
authors.forename: A V
authors.initials: AV
authors.lastname: Schally
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D010903:Pituitary Gland, Anterior; D051381:Rats; D017207:Rats, Sprague-Dawley; D011986:Receptors, Somatotropin / Q000378:metabolism; D017337:Sermorelin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C106656:MZ 5-156; D010446:Peptide Fragments; D010455:Peptides; D011986:Receptors, Somatotropin; D017337:Sermorelin; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; C059148:somatotropin releasing hormone (1-29)