摘要:

AbstractWe report the synthesis, binding affinities to the recombinant human somatostatin receptors, and structure‐activity relationship studies of compounds related to the cyclic hexapeptide,c‐[Pro6‐Phe7‐D‐Trp8‐Lys9‐Thr10‐Phe11], L‐363,301 (the numbering in the sequence refers to the position of the residues in native somatostatin). The Pro residue in this compound is replaced with the arylalkyl peptoid residues Nphe (N‐benzylglycine), (S)βMeNphe [(S)‐N‐[(α‐methyl)benzyl]glycine]or (R)βMeNphe [(R)‐N‐[(α‐methyl)benzyl]glycine]andl‐1‐naphthylalanine is incorporated into either position 7 or 11 of the parent compound. The synthesis and binding data of the Nnal6([N‐naphthylmethyl]glycine) analog of L‐363,301 is also reported. The incorporation of the Nnal residue into position 6 of L‐363,301 resulted in an analog with weaker binding affinities to all hsst receptors but enhanced selectivity towards the hsst2 receptor compared with the parent compound. The other compounds bind effectively to the hsst2 receptor but show some variations in the binding to the hsst3 and hsst5 receptors resulting in different ratios of binding affinities to the hsst5 and hsst2 or hsst3 and hsst2, respectively. The incorporation of the Nphe residue into position 6 and the Nal residue into position 7 of L‐363,301 led to a compound which binds potently to the hsst2 and has increased selectivity towards this receptor (weaker binding to hsst3 and hsst5 receptors) compared with the parent compound. The analogs with β‐methyl chiral substitutions in the aromatic peptoid side chain and Nal in position 7 or 11 bind effectively to the hsst2 and hsst5 receptors. They exhibit similar ratios of binding affinities to the hsst5 and hsst2 receptors as observed for L‐363,301. There are however minor differences in binding to the hsst3 receptor among these analogs. These studies allow us to investigate the influence of additional hydrophobic groups on the binding activity to the isolated human somatostatin receptors and the results are important for the design of other somatostatin analogs. Copyright © 1

ISSN:1075-2617    

DOI:10.1002/(SICI)1099-1387(199903)5:3<113::AID-PSC176>3.0.CO;2-N

出版商:John Wiley&Sons, Ltd.    

年代:1999

数据来源: WILEY

摘要:

AbstractDKP formation is a serious side reaction during the solid‐phase synthesis of peptide acids containing either Pro or Gly at theC‐terminus. This side reaction not only leads to a lower overall yield, but also to the presence in the reaction crude of several deletion peptides lacking the first amino acids. For the preparation of protected peptides using the Fmoc/tBu strategy, the use of a ClTrt‐Cl‐resin with a limited incorporation of theC‐terminal amino acid is the method of choice. The use of resins with higher loading levels leads to more impure peptide crudes. The use of HPLC‐ESMS is a useful method for analysing complex samples, such as those formed whenC‐terminal Pro peptides are prepared by non‐optimized solid‐phase strategies. Copyright © 1999 European Peptide Society and Jo

ISSN:1075-2617    

DOI:10.1002/(SICI)1099-1387(199903)5:3<131::AID-PSC183>3.0.CO;2-Z

出版商:John Wiley&Sons, Ltd.    

年代:1999

数据来源: WILEY

摘要:

AbstractWe report the solid‐phase synthesis and some pharmacological properties of 23 new analogs of arginine vasopressin (AVP) which have the Phe3residue replaced by a broad variety of amino acids. Peptides 1–9 have at position 3: (1) the mixed aromatic/aliphatic amino acid thienylalanine (Thi) and the aliphatic amino acids; (2) cyclohexylalanine (Cha); (3) norleucine (Nle); (4) Leu; (5) norvaline (Nva); (6) Val; (7) alpha‐aminobutyric acid (Abu); (8) Ala; (9) Gly. Peptides 10–23 have at position 3: the aromatic amino acids, (10) homophenylalanine (Hphe); (11) Tyr; (12) Trp; (13) 2‐naphthylalanine (2‐Nal); the conformationally‐restricted amino acids (14) Pro; (15) 2‐aminotetraline‐2‐carboxylic acid (Atc); the polar amino acids (16) Ser; (17) Thr; (18) Gln; and the charged amino acids (19) Asp; (20) Glu; (21) Arg; (22) Lys; (23) Orn. All 23 new peptides were evaluated for agonistic and, where appropriate, antagonistic activities inin vivoantidiuretic (V2‐receptor) and vasopressor (V1a‐receptor) assays and inin vitro(no Mg2+) oxytocic assays. The corresponding potencies (units/mg) in these assays for AVP are: 323±16; 369±6 and 13.9±0.5. Peptides 1–9 exhibit the following potencies (units/mg) in these three assays: (1) 379±14; 360±9; 36.2±1.9; (2) 294±21; 73.4±2.7; 0.33±0.02; (3) 249±28; 84.6±4.3; 4.72±0.16; (4) 229±19; 21.4±0.6; 2.1±0.2; (5) 134±5; 31.2±0.9; 28.4±0.2; (6) 114±9; 45.3±2.3; 11.3±1.6; (7) 86.7±2.5; 4.29±0.13; 0.45±0.03; (8) 15.5±1.5; 0.16±0.01; ∼0.02; (9) 3.76±0.03;<0.02;in vitrooxytocic agonism was not detected. These data show that the aliphatic amino acids Cha, Nle, Leu, Nva and Val are well‐tolerated at position 3 in AVP with retention of surprisingly high levels of antidiuretic activity. Peptides 2–9 exhibit significant gains in both antidiuretic/vasopressor (A/P) and antidiuretic/oxytocic (A/O) selectivities relative to AVP. [Thi3]AVP appears to be a more potent antidiuretic and oxytocic agonist than AVP and is equipotent with AVP as a vasopressor agonist. The antidiuretic potencies of peptides 10–23 exhibit drastic losses relative to AVP. They range from a low of 0.018±0.001 units/mg for the Lys3analog (peptide 22) to a high of 24.6±4.6 units/mg for the Hphe3analog (peptide 10). Their vasopressor potencies are also drastically reduced. These range from a low of<0.002 units/mg for peptide 22 to a high of 8.99±0.44 units/mg for the Atc3analog (peptide 15). Peptides 10–23 exhibit negligible or undetectablein vitrooxytocic agonism. The findings on peptides 10–23 show that position 3 in AVP is highly intolerant of changes with aromatic, conformationally‐restricted, polar and charged amino acids. Furthermore, these findings are in striking contrast to our recent discovery that position 3 in the potent V2/V1a/OT antagonist d(CH2)5d‐Tyr(Et)2VAVP tolerates a broad latitude of structural change at position 3 with many of the same amino acids, to give excellent retention of antagonistic potencies. The data on peptides 1–4 offer promising clues to the design of more potent and selective AVP V2ago

ISSN:1075-2617    

DOI:10.1002/(SICI)1099-1387(199903)5:3<141::AID-PSC180>3.0.CO;2-6

出版商:John Wiley&Sons, Ltd.    

年代:1999

数据来源: WILEY

摘要:

AbstractThe search for heterocyclic scaffolds for the design of non‐peptidic and highly selective agonists or antagonists of peptide hormone receptors led to 4‐N‐benzyl‐2,3,4,5,6,7‐hexahydro‐1H‐1,4,7‐benzotriazonin‐2,6‐dione with a 9‐membered core structure as a new low mass lead compound that exhibits submicromolar antagonistic activity at the CCK‐A receptor with a 54‐fold selectivity over the CCK‐B/gastrin receptor. Copyright © 1999 European Peptide Soci

ISSN:1075-2617    

DOI:10.1002/(SICI)1099-1387(199903)5:3<155::AID-PSC195>3.0.CO;2-E

出版商:John Wiley&Sons, Ltd.    

年代:1999

数据来源: WILEY