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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