| Betidamino acid scan of the GnRH antagonist acyline. | |
| | |
MedLine Citation:
|
PMID: 9371239 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Strong clinical evidence suggests that GnRH antagonists will replace GnRH agonists in a number of indications because of their ability to inhibit gonadotropin secretion as long as an adequate concentration of the analogue is present in the circulation whereas superagonists will take approximately 2 weeks to desensitize the gonadotrophs. Until recently, antagonists were either too weak and/or would release histamine. Azaline B {[Ac-D2Nal1,D4Cpa2,D3Pal3, 4Aph5(atz),D4Aph6(atz),ILys8,DAla10] GnRH} and long-acting members of the azaline family {Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(X)-D4Aph(Y) -Leu-ILys-Pro-DAla-NH2}, however, appear to be promising drug candidates. Because these antagonists tend to form gels (due to the formation of beta-sheet structures) and, as a result, are not readily amenable to formulation for long-term delivery, we have investigated ways of increasing hydrophilicity while retaining high potency and lack of histamine releasing activity. Betidamino acids (a contraction of "beta" position and "amide") are N'-monoacylated (optionally, N'-monoacylated and N-mono- or N,N'-dialkylated) aminoglycine derivatives in which each N'-acyl/alkyl group may mimic naturally occurring amino acid side chains or introduce novel functionalities. We have used unresolved N alpha-Boc,N'alpha-Fmoc-aminoglycine, and N alpha-Boc,N'alpha-(CH3)Fmoc-aminoglycine as templates for the introduction of betidamino acids in acyline (Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(Ac)-D4Aph(A c)-Leu-Ilys-Pro-DAla-NH2), a long acting member of the azaline B family, to test biocompatibility of these betide derivatives. Diastereomeric peptides could be separated using RP-HPLC in most cases. Biological results obtained in vitro (binding affinity to rat pituitary gland membranes) and in vivo (rat antiovulatory assay, AOA) indicate in most cases small differences in relative potencies (< 5-fold) between the D- and L-nonalkylated betidamino acid-containing acylines. Importantly, most betide diastereomers have high affinity for the GnRH receptor and were equipotent with acyline in the AOA. Greater differences in affinity and potency between diastereomers were observed after introduction of a methyl group on the side chain nitrogen ("beta" position) of the same analogues, with one of the diastereomer having an affinity and a potency in the AOA equivalent to that of acyline. These results suggest that chirality at the alpha-carbon coupled to side chain orientation is important for receptor recognition. The duration of action of some of the most potent analogues was also determined in the castrated male rat in order to measure the extent (efficacy and duration of action) of inhibition of luteinizing hormone release. Data suggest that introduction of a betidamino acid results in reduction of duration of action. Also, introduction of betidamino acids results in peptides with increased hydrophilicity (as determined by elution times on C18 silicas at pH 7.3) compared to that of the parent compound. N'-Methyl substitution results in parallel increase in retention times on C18 silicas as expected. |
| | |
Authors:
|
G Jiang; C Miller; S C Koerber; J Porter; A G Craig; S Bhattacharjee; P Kraft; T P Burris; C A Campen; C L Rivier; J E Rivier |
Related Documents
:
|
17034119 - Discovery of phenyl acetic acid substituted quinolines as novel liver x receptor agonis... 12361389 - Development of novel edg3 antagonists using a 3d database search and their structure-ac... 12697169 - Cantharidin analogues: synthesis and evaluation of growth inhibition in a panel of sele... 430479 - Pharmacologically active sulfoximides: 5-hexyl-7-)s-methylsulfonimidoly) xanthone-2-car... 6861999 - Researches on antibacterial and antifungal agents. i. analogs of nalidixic acid with a ... 16616499 - Synthesis of new class dipeptide analogues with improved permeability and antithromboti... 18956869 - Total synthesis of (+/-)-lysergic acid, lysergol, and isolysergol by palladium-catalyze... 11320119 - Insertion of fluorescent fatty acid probes into the outer membranes of the pathogenic s... 2305019 - Effects of hypnotic, placebo, and salicylic acid treatments on wart regression. |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
|
Title: Journal of medicinal chemistry Volume: 40 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 1997 Nov |
Date Detail:
|
Created Date: 1997-12-15 Completed Date: 1997-12-15 Revised Date: 2007-11-14 |
Medline Journal Info:
|
Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: UNITED STATES |
Other Details:
|
Languages: eng Pagination: 3739-48 Citation Subset: IM |
Affiliation:
|
Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, California 92037, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Amides
/
chemical synthesis,
metabolism,
pharmacology Amino Acids / analysis*, chemical synthesis, pharmacology Animals Female Gonadotropin-Releasing Hormone / analogs & derivatives, antagonists & inhibitors* Male Oligopeptides / chemical synthesis*, metabolism, pharmacology* Pituitary Gland, Anterior / drug effects, metabolism Rats |
| Grant Support | |
ID/Acronym/Agency:
|
DK 26741/DK/NIDDK NIH HHS; HD 13527/HD/NICHD NIH HHS; HL 41910/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Amides; 0/Amino Acids; 0/Oligopeptides; 170157-13-8/acyline; 33515-09-2/Gonadotropin-Releasing Hormone |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: 1,4-disubstituted anthracene antitumor agents.
Next Document: 1-[(omega-aminoalkyl)amino]-4-[N-(omega-aminoalkyl)carbamoyl]-9-oxo-9, 10-dihydroacridines as interc...