ABSTRACT
Thyrotropin-releasing hormone (TRH) analogues which show relative selectivity for action in the central nervous system have been recognized. Practical syntheses for three of these TRH analogues which show the greatest selectivity, less than Aad-His-Tzl-NH2 (5), less than Glu-His-Pip-OMe (2), and less than Aad-His-Pro-NH2 (6), are described. The first two were prepared by solution methods of peptide synthesis. Compound 6 was prepared by the solid-phase method. Problems of histidine racemization, facile diketopiperazine formation, and instability of acylated thiazolidine carboxylic acid derivatives under acidic conditions have been minimized in order to attain optimal yields. Physical properties such as pK, NMR shifts, and circular dichroism have been examined as they might relate to biological activity and peptide conformation.
Subject(s)
Central Nervous System/drug effects , Thyrotropin-Releasing Hormone/analogs & derivatives , Pyrrolidonecarboxylic Acid/analogs & derivatives , Structure-Activity Relationship , Thiazolidines , Thyrotropin-Releasing Hormone/chemical synthesis , Thyrotropin-Releasing Hormone/pharmacology , Thyroxine/metabolism , Triiodothyronine/metabolismABSTRACT
Less than Glu-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn, a proposed serum thymic factor, has been synthesized. The protected precursor, less than Glu-Ala-Lys(i-Noc)-ser(Bzl)-Gln-Gly-Gly-Ser(Bzl)-Asn, was prepared by a combination of solid phase and solution methods. The benzyl blocking groups were removed by HF and the i-Noc blocking group was removed by catalytic hydrogenation.
Subject(s)
Thymus Hormones/chemical synthesis , Amino Acid Sequence , Methods , Oligopeptides/chemical synthesisSubject(s)
Indoleacetic Acids/chemical synthesis , Benzene , Chemistry, Pharmaceutical , Chlorine , MethylationABSTRACT
A model for a biologically active conformation of somatostatin is proposed. This model is based primarily on the biological results obtained with novel bicyclic somatostatin analogs having a covalent bridge replacing the side chains of residues 5 and 10, 6 and 11, and 5 and 12, respectively, rather than on physical measurements on the hormone in solution. The high activity of an analog in which Phe6 and Phe11 are replaced by cystine provides evidence that these phenylalanines stabilize the biologically active conformer through "hydrophobic bonding" but do not directly interact with the receptor. The synthesis of the novel bicyclic analogs of somatostatin and the effects of these on the inhibition of secretion of insulin, glucagon, growth hormone, and gastric acid are described.
Subject(s)
Hormones , Somatostatin/analogs & derivatives , Animals , Biological Assay , Gastric Juice/metabolism , Glucagon/metabolism , Growth Hormone/metabolism , Insulin/metabolism , Insulin Secretion , Pentagastrin/pharmacology , Protein Conformation , Rats , Receptors, Cell Surface/metabolism , Somatostatin/metabolism , Structure-Activity RelationshipABSTRACT
A cyclic hexapeptide analog of somatostatin, cyclo-(Pro-delta z-Phe-D-Trp-Lys-Thr-Phe) (II) has been synthesized by a combination of solid phase and solution methodology. It shows a potency for inhibition of growth hormone release in vitro about one-tenth that of the corresponding saturated analog, cyclo-(Pro-Phe-D-Trp-Lys-Thr-Phe) (I). N.m.r. studies indicate comparable backbone conformations for analogs I and II. However, the sum of our findings from biological evaluation and solution physical data suggest that on the receptor the position-7 phenyl ring of I is adopting a conformation which differs from that of one of the major solution conformers defined previously by n.m.r. studies.