Antiovulatory Potency and Conformation of an Antagonist of the Luteinizing Hormone-Releasing Hormone Having Six D-Amino Acids

Folkers, Karl; Bowers, Cyril Y.; Momany, Frank A.; Friebel, Klaus; Kubiak, Teresa M.; Mahera, Joseph

doi:10.1515/znb-1982-0716

Cited by 12 publications

(2 citation statements)

References 7 publications

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“…The analogs were synthesized by solidphase method as described [7]. Purification of the crude peptides was achieved by an appropriate choice of sequences from the following methods: (A) gel filtration over Sephadex G-25 in 20% acetic acid; (B) chromatography over silica gel 60 (230 to 400 mesh) in n-butanol-acetic acid-water, 4:1:5 upper phase; (C) semipreparative high pressure liquid chromatography on a /^-Bondapak Cis column in linear gradients of buffer A (0.05 M ammonium acetate, pH 5.0), and buffer B (20% buffer A/80% acetonitrile).…”

Section: Methodsmentioning

confidence: 99%

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

Folkers

Bowers

Kubiak

et al. 1983

Zeitschrift Für Naturforschung B

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Abstract Analogs of the luteinizing hormone releasing hormone (LHRH) having a moiety (D-Qal-) of β-(3-quinolyl)-D-α-alanine were synthesized toward more effective inhibitors of ovulation. [N-Ac-pCl-D-Phe1,2, D-3-Pal3, D-3-Qal6, D-Ala10]-LHRH was the most effective, and had an antiovulatory activity of 40% at 1 μg/rat. D-3-Qal6 was as effective as D-Trp6 in combination with N-Ac-3⊿Pro1, pF-D-Phe2, D-Trp3. D-Arg6 was superior to D-3-Qal6) in combination with N-Ac-pCl-D-Phe1,2, D-Trp3 (or D-3-Pal3), D-Ala10. The introduction of D-3-Qal3, D-His3 and D-Arg3 in comparable analogs caused substantial loss of activities.

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Section: Methodsmentioning

confidence: 99%

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

Folkers

Bowers

Kubiak

et al. 1983

Zeitschrift Für Naturforschung B

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“…Peptide Synthesis. The peptides were synthesized by the solid-phase method on a Beckman model 990 peptide synthesizer (18). After attachment of the first amino acid was completed, the resin was acetylated by a 25% (vol/vol) acetic anhydride solution in dichloromethane/pyridine.…”

mentioning

confidence: 99%

Spantide II, an effective tachykinin antagonist having high potency and negligible neurotoxicity.

Folkers

Feng

Asano

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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Spantide (D-Arg'-Pro2-Lys3-Pro4-Glns-Gln6-D-Trp7-Pheg-D-Trp9-Leuu'-Leuu1-NH2) was introduced as a tachykinin antagonist in 1984 and has served as a starting point in the design of new antagonists that have proven to be more effective and have exhibited no neurological side effects. The most remarkable and unpredictable structural change that significantly increased potency was deletion of a methylene group by changing Gln6 to Asn6. On the basis that D-Arg' and Lys3 of spantide contribute to neurological side effects, many and NMe is norleucine], which is a potent antagonist without neurotoxicity. Spantide H, an undecapeptide, has a total ofseven substitutions in the sequence of substance P, consisting of two natural L amino acids, and one unnatural L amino acid, and four unnatural D amino acids. The w-and ar-bond amino acid substituents of substance P and spantide II are compared toward a future understanding of the essential substituents for mechanism and inhibition binding. Spantide II has five u-bond and six a-bond amino acid moieties, and substance P has two ur-bond and nine or-bond moieties.During the last decade, increasingly potent tachykinin antagonists have become available (1, 2). By 1984, the substance P (SP) analogue [D-Arg1,D-Trp7 9,Leu11]SP was introduced; it had a pA2 value (negative logarithm of antagonist concentration producing a 2-fold shift of the agonist concentration-activity curve) of 7.1 and was named spantide (3). It was used by many pharmacological investigators as a model antagonist in the periphery. Also, spantide served as a reference antagonist for the chemical design of new analogues to provide even more effective inhibitors. By 1986, these efforts had led to the replacement of Glns with aromatic D amino acids (4)

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Biomedical Polypeptides — A Wellspring of Pharmaceuticals

Samanen

1985

Bioactive Polymeric Systems

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Antiovulatory Potency and Conformation of an Antagonist of the Luteinizing Hormone-Releasing Hormone Having Six D-Amino Acids

Cited by 12 publications

References 7 publications

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

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

Spantide II, an effective tachykinin antagonist having high potency and negligible neurotoxicity.

Biomedical Polypeptides — A Wellspring of Pharmaceuticals

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