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1995 (1)
1991 (1)
1Author    Anders Ljungqvista, Dong-M Ei Feng3, Cyril Bowers, WilliamA H Ookc, Karl Folkers3Requires cookie*
 Title    Design, Synthesis and Biological Evaluation of Antagonists of LHRH by Criteria of Potency, Safety and Solubility  
 Abstract    Some analogs o f Antide and congeners with higher water solubility have been synthesized by substitutions in positions 1, 5 or 6 with hydrophilic residues. In position 1, D -3 -Q a l has been incorporated in four peptides and D -3 -P a l in one peptide. In positions 5 and 6, D and L -3 -P a l, PzAla and (DSer)Lys have been tried. In one peptide, D -(A cD S er)L y s was substi­ tuted in position 6. M ost o f the new analogs had lower AOA (antiovulatory activity) than the parent com ­ pounds but three potent analogs were identified. The first one, [N -A c -D -3 -Q a l',D p C lP h e 2,D -3 -P a l3,c-PzA C A la5,D -P ic L y s 6,ILys8,D -A l a l0]-L H R H , had 55% A O A at 0.25 ng and 100% at 0.5 /ug. Its E D 50 for in vitro histamine release was 171 ± 17 ^g/m l which is an increase from 4 9 ± 4 .8 >ug/ml for the parent com pound with N -A c -D -2 -N a l [1], The second analog, [N -A c -D -2 -N a l',D p C lP h e 2,D -3 -P a l3,PicLys5,D -(D S e r)L y s6,ILys8,D -A l a 10]-L H R H , had 69% A OA at 0.25 /ug and 95% at 0.5 fig. This analog released somewhat more histamine than the parent analog featuring D -P ic L y s6, the E D S0 being 18 //g/m l compared to 93 ± 11 for the parent analog. The third analog is: [ N -A c -D -2 -N a t 1, D pClPhe2,D -3 -P a l3,c-PzA C A la5,D -P z A la 6,ILys8,D A la ']-L H R H . The AOA for this analog was 63% at 0.25 //g and the E D 50 for histamine release 8 8 ± 6 .4 ^g/ml. histamine from mast cells [1], These features in­ clude a group of hydrophobic amino acids at the N-terminal and strongly basic residues in positions 6 and 8 , notably D -Arg6,Arg8. A prime example o f this class o f antagonists is [N -A c -D -2 -N a l',D -4 F -P h e 2 ,D -T rp 3, D -A rg 6] -LH R H [2], It was recently shown that some antag­ onists bind to rat peritoneal mast cells and mem­ brane preparations and that the binding was relat­ ed to the release of histamine [3]. We recently developed Antide (analog 1, Table III) which lacked strongly basic residues and which showed high potency and negligible histamine re­ lease [4], F urther evaluation of the anaphylactoid activity o f Antide concluded that Antide "repre­ sents a new generation of LH R H antagonists with an improved safety m argin" [5]. Prolonged duration of inhibition of gonado­ tropin secretion in overectomized monkeys using single [6 ] or multiple [7] doses of Antide has also been established. The same group observed a long-term supres-sion o f testosterone secretion in male monkeys after a single dose of Antide [8 ]. 
  Reference    Z. Naturforsch. 46b, 1231 (1991); received March 1 1991 
  Published    1991 
  Keywords    LH R H -A ntagonists, Antiovulatory Activity, Histam ine Release, Solubility 
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 TEI-XML for    default:Reihe_B/46/ZNB-1991-46b-1231.pdf 
 Identifier    ZNB-1991-46b-1231 
 Volume    46 
2Author    Anna Janecka3, StevenK. Oerberb, Tomasz Janecki3, Cyril Bowersc, Karl Folkers3Requires cookie*
 Title    N5-PyrazinylcarbonyIornithine, an Effective Substituent for Position 5 of Antagonists of LHRH  
 Abstract    Com puter modeling was used to find an effective substituent for position 5 in antagonists of the luteinizing hormone-releasing hormone (LHRH). In particular, it was desired to replace ds-3-(4-pyrazinylcarbonylaminocyclohexyl)alanine in position 5 because this sub­ stituent is laborious to synthesize. Calculations revealed that N5-pyrazinylcarbonylornithine (PzOrn) should be a suitable substitute for cPzACAla, with N6-pyrazinylcarbonyllysine (PzLys) being a second choice. Twelve analogs were synthesized in four series with DNal or DQal in position 1 and ILys or Arg in position 8. Biological assays validated the calculations and show that antagonists with PzOrn are more potent in antiovulatory assay than antag­ onists with PzLys. The antagonists with PzOrn were comparable in AOA with antagonists with cPzACAla. What is also im portant, antagonists with PzOrn released significantly less histamine than those with cPzACAla. 
  Reference    Z. Naturforsch. 50b, 147—150 (1995); received April 27 1994 
  Published    1995 
  Keywords    LH RH Antagonists, Com puter Modeling, Antiovulatory Activity, Histamine Release, Solid Phase Peptide Synthesis 
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 TEI-XML for    default:Reihe_B/50/ZNB-1995-50b-0147.pdf 
 Identifier    ZNB-1995-50b-0147 
 Volume    50