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1Author    Karl Folkers, CyrilY. Bowers+, WilsonB. Lutz, Klaus Friebel, Teresa Kubiak, Bernhard Schircks, Georg RampoldRequires cookie*
 Title    Synthesis and Bioassay of Antagonists of the Luteinizing Hormone Releasing Hormone Having the Azagly 10 Moiety  
 Abstract    Seven new analogs of the luteinizing hormone releasing hormone (LHRH), having an Azagly 10 moiety, and three corresponding Gly 10 -analogs were synthesized for bioassay and comparison of inhibitory potencies. This study was toward a possible advantage of the Azagly 10 moiety to minimize C-terminal degradation, in vivo. Of the three procedures which were studied to achieve Azagly 10 -peptides, the reaction of cyanate ion with hydrazides was the most favorable. Variations of substitution in position 1 were also studied. The data from the antiovulatory assay showed that an Azagly 10 moiety may not depress activity, and may allow equal or even higher activity than the Glv 10 moiety, depending on the analog. [N-Ac-D-Thr 1 , D-p-Cl-Phe 2 , D-Trp 3 -6 , Azagly 10 ] LHRH was more inhibitory than the corresponding Gly 10 -analog. Based on pairs of analogs, the following relationships appeared: (1) N-Ac-D-Thr 1 was more effective than N-Ac-jo-Cl-Phe 1 ; (2) The L-configuration of Ala as N-Ac-Ala 1 -was more effective than the D—; (3) N-Ac-Ala 1 appeared more effective than the N-Ac-D-Thr 1 ; (4) D-Trp 6 appeared more effective than D-Phe 6 . In an ultimate clinical use of an antagonist of LHRH to block ovulation, the Azagly 10 moiety may be advantageous for limitation of enzymatic degradation. 
  Reference    Z. Naturforsch. 37b, 1075—1081 (1982); received March 23 1982 
  Published    1982 
  Keywords    Antagonist, Luteinizing Hormone Releasing Hormone, Ovulation, Peptides, Azaglycine 
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 TEI-XML for    default:Reihe_B/37/ZNB-1982-37b-1075.pdf 
 Identifier    ZNB-1982-37b-1075 
 Volume    37 
2Author    Karl Folkers, CyrilY. Bowers, Teresa Kubiak, Janusz StepinskiRequires cookie*
 Title    Synthesis and Antiovulatory Activities in Rats of Analogs of the Luteinizing Hormone Releasing Hormone Having a Moiety of /?-(3-Quinolyl)-D-a-alanine in Positions 3 and 6  
 Abstract    Analogs of the luteinizing hormone releasing hormone (LHRH) having a moiety (D-Qal-) of/3-(3-quinolyl)-D-a-alanine were synthesized toward more effective inhibitors of ovulation. [N-Ac-^Cl-D-Phe 1 -2 , D-3-Pal 3 , D-3-Qal 6 , D-Ala 10 ]-LHRH was the most effective, and had an antiovulatory activity of 40% at 1 /ig/rat. D-3-Qal 6 was as effective as D-Trp 6 in combination with N-Ac-3 z1 Pro 1 , ^oF-D-Phe 2 , D-Trp 3 . D-Arg 6 was superior to D-3-Qal 6) in combination with N-Ac-^Cl-D-Phe 1 ' 2 , D-Trp 3 (or D-3-Pal 3), D-Ala 10 . The introduction of D-3-Qal 3 , D-His 3 and D-Arg 3 in comparable analogs caused sub-stantial loss of activities. Abbreviations D-3-Pal = /S-(3-pyridyl)-D-a-alanine; D-3-Qal = ß-(3-quinolyl)-D-a-alanine; BOC = fertf-butyloxy-carbonyl; ÄOC = tferf-amyloxycarbonyl; DCC = N,N'-dicyclohexylcarbodiimide; 3 ZlPro = 3,4-dehydro-L-proline; pF-D-Phe — yara-fluoro-D-phenylalanine; ^Cl-D-Phe = ^»am-ehloro-D-phenylalanine; Ac = acetyl, HPLC = high performance liquid chromato-graphy. 
  Reference    Z. Naturforsch. 38b, 1253—1256 (1983); received June 27 1983 
  Published    1983 
  Keywords    Ovulation, Hormone, Antagonist, Quinolylalanine, Luteinizing Hormone Releasing Hormone 
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 TEI-XML for    default:Reihe_B/38/ZNB-1983-38b-1253.pdf 
 Identifier    ZNB-1983-38b-1253 
 Volume    38 
3Author    Karl Folkers, CyrilY. Bowers, Yin-Zeng Liu, Xiao Shao-Bo, Hong-Ming Shieh, Chu Ji-YuRequires cookie*
 Title    Antagonists of the Luteinizing Hormone Releasing Hormone with Emphasis on Amino Acids in Position Five  
 Abstract    Seventeen analogs of the luteinizing hormone releasing hormone (LHRH) have been syn-thesized, bioassayed, and compared for antiovulatory activity (AOA) in rats. The emphasis of design was replacement of Tyr 5 of LHRH. Position 5 has not been extensively studied. [N—Ac—D-2-Nal 1 , D-pClPhe 2 , D-3-Pal 3 , D-Arg 6 , D—Ala 10 ]-LHRH was the baseline for new designs. Comparison of the AOA's of the 17 analogs with the baseline revealed the two peptides with Phe 5 and 3-Pal 5 had equivalent AOA's, and were the best of the 17, and about 45% more potent than the baseline. Analogs with pClPhe 5 , oClPhe 5 , a-MepClPhe 5 , 2-Nal 5 , Trp 5 , and His 5 were less potent than the Phe 5 -and 3-Pal 5 -analogs. Based on the Phe 5 -analog, eight other analogs were synthesized with changes in positions 1, 2, 3 and 7 and although none were better than the baseline, 5/8 showed 20—60% AOA's at 250 ng and revealed optimum positions for new designs. 
  Reference    Z. Naturforsch. 40b, 313—316 (1985); received August 20 1984 
  Published    1985 
  Keywords    Peptide, Hormone, Ovulation, Luteinizing Hormone Releasing Hormone, Antagonist 
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 TEI-XML for    default:Reihe_B/40/ZNB-1985-40b-0313.pdf 
 Identifier    ZNB-1985-40b-0313 
 Volume    40 
4Author    Karl Folkers, Cyril Bowers, Pui-FunL. Tang, Minoru Kobota, Xiao Shao-Bo, Wolf­ Gang Bender, Liu Yin-ZengRequires cookie*
 Title    Relative Potencies of Antagonists of the Luteinizing Hormone Releasing Hormone with Lys8 and Arg8 and Substitutions in Positions 3 ,5 ,6 ,7 and 8d-Ala10] — N H 2 and [N -A c—D-2  
 Abstract    Antagonists of the luteinizing hormone releasing hormone (L H R H) of increased potency is a goal for control of ovulation. In the design and synthesis of 26 decapeptides, emphasis was given to analogs with Lys8 and Arg8 and with various substitutions in positions 3, 5, 6, 7 and 8. Two antagonists, [N — A c—D-2-Nal]-N H 2 showed 80-85% antiovulatory activity (A O A) at 0.25 (ig in the rat. The latter antagonist showed 60% A O A at 0.125 ^.g. O f four pairs of analogs with Arg8 and Lys8, respectively, two pairs favored Lys8 over Arg8 for potency. One pair showed negligible difference and another pair favored Arg8 over Lys8. There is specificity of substitution for potency. In other antagonists, d -3-Pal3, Tyr5 or Phe5, D-Arg6 and Leu7 or Nie7 or Val7 and Arg8 were variously effective substitutions for increase of potency and reduction of histamine release. 
  Reference    Z. Naturforsch. 41c, 1087—1091 (1986); received June 10 1986 
  Published    1986 
  Keywords    Luteinizing Hormone Releasing Hormone, Ovulation, Peptide, Antagonist, Histamine Release 
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 TEI-XML for    default:Reihe_C/41/ZNC-1986-41c-1087.pdf 
 Identifier    ZNC-1986-41c-1087 
 Volume    41 
5Author    Karl Folkers, CyrilY. Bowers, Frank Momany, KlausJ. Friebel, Teresa Kubiak, Joseph MaherRequires cookie*
 Title    Antiovulatory Potency and Conformation of an Antagonist of the Luteinizing Hormone-Releasing Hormone Having Six D-Amino Acids  
 Abstract    Thr 1 ,D-Phe 2 ,D-Trp 3 > 6 ]-LHRH was the model antagonist of LHRH, which was the basis for tho design, synthesis and bioassay of seven peptides having four, five and six D-amino acids, which resulted from three single, three double, and one triple introductions of D-amino acids in positions 4, 5 and 8 of the model. Only the analog with six D-amino acids, [N-Ac-Thr 1 ,D-Phe 2 ,D-Trp 3 ,D-Ser^D-Tyr 5 ,D-Trp 6 ,D-Arg 8 ]-LHRH, had antiovulatory activity which was higher than that of the model antagonist, i.e., 70% antiovulatory activity at 25 //g/rat compared with 50% activity at 50 //g/rat, respectively. Empirical energy calculations gave a conformational structure for [N-Ac-Thr 1 ,D-Phe 2 ,D-Trp 3 , D-Ser 4 ,D-Tyr 5 ,D-Ar£' 6 ,D-Arg 8 ]-LHRH which is similar to that calculated for previous potent antagonists. These results are a basis of new designs of antagonists having D-sub-stituents in up to ten positions toward effective inhibitors of ovulation by the parenteral and oral routes of administration. 
  Reference    Z. Naturforsch. 37b, 872—876 (1982); received February 23 1982 
  Published    1982 
  Keywords    Luteinizing Hormone-Releasing Hormone, Antagonist, Antiovulation, Conformation, Contraception [N-Ac- 
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 TEI-XML for    default:Reihe_B/37/ZNB-1982-37b-0872.pdf 
 Identifier    ZNB-1982-37b-0872 
 Volume    37 
6Author    Karl Folkers, Cyril Bowers, Xiao Shao-Bo, Pui-Fun, Louisa Tang, Minoru Kubota, Janusz Stepinski, Teresa KubiakRequires cookie*
 Title    Activities of Antagonists of the Luteinizing Hormone Releasing Hormone with Emphasis on Positions 1, 5 and 6 and on Positions 1, 2 and 3  
 Abstract    Analogs of the luteinizing hormone releasing hormone (LHRH) which are antagonists for controlling ovulation require potency and negligible release of histamine as a side effect. Forty analogs were designed, synthesized and bioassayed in two groups with emphasis upon positions 1, 5 and 6 and upon positions 1, 2 and 3. N-Ac-D-2-Nal 1 , D-pClPhe 2 , D-3-Pal 3 , Ser 4 , Tyr 5 . D-Lys 6 , 
  Reference    (Z. Naturforsch. 42b, 101—106 [1987]; received July 18 1986) 
  Published    1987 
  Keywords    Luteinizing Hormone Releasing Hormone, a«f/-Ovulatory Activity, Peptide, Antagonist, Histamine Release 
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 TEI-XML for    default:Reihe_B/42/ZNB-1987-42b-0101.pdf 
 Identifier    ZNB-1987-42b-0101 
 Volume    42