Oxytocin analogues with amide groups substituted by tetrazole groups in position 4, 5 or 9
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Eleven oxytocin analogues substituted in position 4, 5 or 9 by tetrazole analogues of amino acids were prepared using solid-phase peptide synthesis method and tested for rat uterotonic in vitro and pressor activities, as well as for their affinity to human oxytocin receptor. The tetrazolic group has been used as a bioisosteric substitution of carboxylic, ester or amide groups in structure-activity relationship studies of biologically active compounds. Replacement of the amide groups of Gln4 and Asn5 in oxytocin by tetrazole analogues of aspartic, glutamic and α-aminoadipic acids containing the tetrazole moiety in the side chains leads to analogues with decreased biological activities. Oxytocin analogues in which the glycine amide residue in position 9 was substituted by tetrazole analogues of glycine had diminished activities as well. The analysis of differences in rat uterotonic activity and in the affinity to human oxytocin receptors of analogues containing either an acidic 5-substituted tetrazolic group or a neutral 1,5- or 2,5-tetrazole nucleus makes it possible to draw some new conclusions concerning the role of the amide group of amino acids in positions 4, 5 and 9 of oxytocin for its activity. The data suggest that the interaction of the side chain of Gln4 with the oxytocin receptor is influenced mainly by electronic effects and the hydrogen bonding capacity of the amide group. Steric effects of the side chain are minor. Substitution of Asn5 by its tetrazole derivative gave an analogue of very low activity. The result suggests that in the interaction between the amide group of Asn5 and the binding sites of oxytocic receptor hydrogen bonds are of less importance than the spatial requirements for this group.
- Atherton E, Sheppard RC (1989) Solid Phase Peptide Synthesis: a Practical Approach. Oxford University Press, London.
- Burger A (1991) Isosterism and bioisosterism in drug design. Prog Drug Res 37: 287-371.
- Butler RN (1984) Tetrazoles. In Comprehensive Heterocyclic Chemistry, vol 5, pp 791-835. Pergamon, Oxford.
- Dekansky J (1952) The quantitative assay of vasopressin. Br J Pharmacol Chemother 7: 567-572.
- Fahrenholz F, Boer R, Crause P, Fritsch G, Grzonka Z (1984) Interaction of vasopressin agonists and antagonists with membrane receptors. Eur J Pharmacol 100: 47-58.
- Gimpl G, Burger K, Fahrenholz F (1997) Cholesterol as modulator of receptor function. Biochemistry 36: 10959-10974.
- Gimpl G, Fahrenholz F (2001) The oxytocin receptor system, structure, function and regulation. Physiol Rev 81: 629-683.
- Hansch C, Leo L (1995) Exploring QSAR. Fundamentals and Applications in Chemistry and Biology, Chapter 13. American Chemical Society, Washington DC.
- Herbst RM, Wilson KR (1957) Apparent acidic dissociation of some 5-phenyltetrazoles. J Org Chem 22: 1142-1145.
- Herr RJ (2002) 5-Substituted-1H-tetrazoles as carboxylic acid isosters: medicinal chemistry and synthetic methods. Bioorg Med Chem 10: 3379-3393.
- Holton P (1948) A modification of the method of Dale and Laidlaw for standardization of posterior pituitary extract. Br J Pharmacol 3: 328-335.
- Kaczmarek J, Smagowski H, Grzonka Z (1979) A correlation of substituent effects with the acidity of aromatic tetrazolic acids. J Chem Soc Perkin Trans 2: 1670-1674.
- Kaiser E, Colescott RC, Bossinger CD, Cook PI (1970) Color test for detection of free terminal amino group in the solid-phase synthesis of peptides. Anal Biochem 34: 595-598.
- Krejči I, Polaček I (1968) Effect of magnesium on the action of oxytocin and a group of analogues on the uterus in vitro. Eur J Pharmacol 2: 393-398.
- Lebl M (1987) Modification of other functional groups. In CRC Handbook of Neurohypophyseal Hormone Analogs, vol I, part 2, Jošt K, Lebl M, Brtnik F, eds, pp 156-159. CRC Press; Boca Raton.
- Manning M, Coy E, Sawyer WH (1970) Solid-phase synthesis of (4-threonine)-oxytocin. A more potent and specific oxytocic agent than oxytocin. Biochemistry 9: 3925-3930.
- Manning M, Grzonka Z, Sawyer WH (1981) Synthesis of posterior pituitary hormones and hormone analogues. In Clinical Endocrinology, vol. 1, Beardwell C, Robertson GL, eds, pp 265-296, Butterworths, London.
- Manning M, Sawyer WH (1985) Development of selective agonists and antagonists of vasopressin and oxytocin. In Vasopressin, Schrier RW, ed, pp. 131-144. Raven Press, New York.
- Manturewicz M, Grzonka Z (2007) Tetrazole analogues of aspartic, glutamic and α-aminoadipic acids and their derivatives with tetrazole ring in side chains useful for solid-phase peptide synthesis. Pol J Chem 81: 2121-2131.
- Manturewicz M, Kosson P, Grzonka Z (2007) Syntheses of Fmoc-α-aminoalkyltetrazoles and tetrazole analogue of Leu-enkephalin. Pol J Chem 81: 1327-1334.
- Munsick RA (1960) Effect of magnesium ions on the response of the rat uterus to neurohypophyseal hormones and analogues. Endocrinology 66: 451-457.
- Rażyńska A, Tempczyk A, Maliński E, Szafranek J, Grzonka Z, Hermann P (1983) Application of mass spectrometry to the study of prototropic equilibria in 5-substituted tetrazoles in the gas phase; experimental evidence and theoretical considerations. J Chem Soc Perkin Trans 2: 379-383.
- Roy U, Gazis D, Dal Pan G, Schwarz I, Roy J (1983) Role of carboxamide groups of the asparagines and glycineamide residue in oxytocin. Syntheses and biological properties of [5-β-cyanoalanine]oxytocin and [9-α-aminoacetonitrile]oxytocin. Int J Pept Protein Res 22: 525-538.
- Rudinger J, Krejči I (1962) Dose-response relations for some synthetic analogs of oxytocin on the isolated uterus. Experientia 18: 585-588.
- Slaninovà J (1987) Fundamental Biological Evaluation. In Handbook of Neurohypophyseal Hormone Analogs, vol 1, part 2, Jošt K, Lebl M, Brtnik F, eds, pp 83-107. CRC Press, Boca Raton.
- Soloff MS, Grzonka Z (1986) Binding studies with rat myometrial and mammary gland membranes on effects of manganese on relative affinities of receptors for oxytocin analogs. Endocrinology 119: 1564-1569.
- Ślusarz MJ, Ślusarz R, Ciarkowski J (2006) Molecular dynamic simulation of human neurohypophyseal hormone receptors complexed with oxytocin-modeling o fan activated state. J Pept Sci 12: 171-179.
- Tarnowska M, Liwo A, Grzonka Z, Tempczyk A (1992) Modified Free-Wilson analysis of the neurohypophyseal hormone analogs II: Analogs of oxytocin-like activity. In QSAR in Design of Bioactive Compounds, Kuchar M, ed, pp 399-436. JR Prous Science, Barcelona.
- Walter R, Skala G, Smith CW (1978) [5-Aspartic acid]-oxytocin: first 5-position neurohypophyseal hormone analogue possessing significant biological activity. J Am Chem Soc 100: 792-793.
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