Synthesis and theoretical conformational studies of gonadotropin-releasing hormone analogs containing tetrahydroisoquinoline carboxylic acid.
A series of analogs of gonadotropin-releasing hormone (GnRH) containing the conformationally restrictive residue tetrahydroisoquinoline carboxylic acid (Tic) or its non-restricted parent phenylalanine were synthesized and evaluated for anti-ovulatory activity in the rat. The series, based on the potent linear parent compound Ac-DNal1-DCpa2-DPal3- Ser4-Tyr5-DPal6-Leu7-Arg8-Pro9-DAla10-NH2, included L-Tic in positions 1, 2, 3, 7 and 9, D-Tic in positions 1, 2, 3, 6 and 9, or D-Phe in positions 2 and 3 for comparison. The most potent analog in this series, with D-Tic in position 6, fully inhibited ovulation at 2.5 micrograms compared to near complete inhibition at 0.5 microgram for the parent compound. A theoretical analysis of the conformational restrictions imposed on mainchain and sidechain torsional angles by the incorporation of Tic was conducted in vacuo using molecular mechanics techniques. Using cyclo(4-10)-[Ac-delta 3Pro1,DCpa2,DTrp3,Asp4,DNal6,Dpr10]- GnRH as a template conformer for which NMR conformational data is available, it was found that the potency of the different analogs correlated with the strain energy required to deform the mainchain and backbone angles of residues to values which would be expected if Tic were present and if the analog assumed the same solution structure. In particular, the effect of DTic at position 6 is to maintain the type II' beta-turn involving residues 5-8 found in active GnRH analogs.
Koerber
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SC
Clayton Foundation Laboratory for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037.
Ibea
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Hagler
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Rivier
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Rivier
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JE
D000595:Amino Acid Sequence; D000818:Animals; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry; D007546:Isoquinolines / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010060:Ovulation / Q000187:drug effects; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines; D013816:Thermodynamics
D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D007987:Gonadotropin-Releasing Hormone; C031270:1,2,3,4-tetrahydroisoquinoline carboxylic acid