Structure–Activity of the Neurohypophyseal Hormones and Analogs and Implications for Hormone–Receptor Interactions

Hruby, Victor J.

doi:10.1016/b978-0-12-452813-0.50012-x

Cited by 12 publications

(11 citation statements)

References 186 publications

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“…The high-affinity binding of the selective oxytocin agonist TG-oxytocin (Manning & Sawyer, 1985) in both systems is the most important finding in this regard. Moreover, the rank order of binding potencies of agonists is largely in agreement with their reported biological activity in the myometrium (Manning & Sawyer, 1985;Hruby, 1986). …”

Section: Discussionsupporting

confidence: 66%

Characterization of oxytocin receptors in rat adenohypophysis using a radioiodinated receptor antagonist peptide

Chadio

Antoni²

1989

Journal of Endocrinology

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Oxytocin may function as a hypothalamic releasing hormone for prolactin and ACTH secretion in the rat. In the present study we have investigated the properties of putative oxytocin receptors in the rat adenohypophysis by radioligand-binding assay. A novel oxytocin receptor antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid),2-(ortho-methyl)-Tyr2-Thr4-Orn8-Tyr9-NH2]-vasotocin (OTA) was radioiodinated by the iodogen method to a specific activity of 0.6 nCi/fmol. The radioiodinated derivative 125I-labelled OTA (125I-OTA) was reacted with membrane suspensions prepared from the uterus or adenohypophysis of female rats which were (a) ovariectomized for 7 days, (b) ovariectomized and treated with 5 micrograms oestradiol-17 beta 48 h before death or (c) implanted with a piece of silicone elastomer tubing containing 50 mg diethylstilboestrol (DES) 5 days before death. In uterine as well as the pituitary membrane suspensions, the radioligand was bound reversibly and with high affinity (dissociation constants 0.2 +/- 0.1 and 0.1 +/- 0.01 nmol/l respectively; mean +/- S.E.M., n = 3) to a single class of sites with limited binding capacity, which varied with the type of pretreatment. Oestradiol-17 beta increased the binding capacity fivefold in the uterus in ovariectomized rats, but only very low specific radioligand binding was found in pituitary preparations from the same animals. Treatment with DES markedly increased the number of receptors in both the uterus and the adenohypophysis. Studies with several agonist and antagonist analogues revealed no difference in the ligand specificity of the uterine and adenohypophysial sites binding 125I-OTA, indicating that they are the same species of receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionsupporting

confidence: 66%

Characterization of oxytocin receptors in rat adenohypophysis using a radioiodinated receptor antagonist peptide

Chadio

Antoni²

1989

Journal of Endocrinology

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“…This had deterred interest in structure-activity relationship studies involving position-5 substitutions. The recognition that oxytocin and vasopressin agonists and antagonists have different structure-activity relationships and use different topographical features for receptor binding (Hruby et al 1983;Manning et al 1984;Chan et al 1986;Hruby, 1986) rekindled interest in investigating the effects of Asn5 substitutions on the activity of oxytocin and vasopressin antagonists. Indeed, it was found that Am5 in oxytocin antagonists could be replaced by a number of hydrophilic amino acids with little or no loss of antagonistic activity (Hill et al 1991).…”

Section: Rationales For Peptide Designmentioning

confidence: 99%

Discovery and design of novel and selective vasopressin and oxytocin agonists and antagonists: the role of bioassays

Çhan¹,

Wo²,

Stoev³

et al. 2000

Experimental Physiology

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Synthetic oxytocin and vasopressin agonists and antagonists have become important tools for research and were instrumental in the identification of the four known receptor subtypes, Via, V,, V,, (V,) and oxytocin, of these peptide hormones. However, the relative lack of receptor selectivity, particularly of the antagonists, has limited their usefulness as experimental probes and their potential as therapeutic agents. We now present some findings from our continuing studies aimed at the design of more selective oxytocin and vasopressin agonists and antagonists and a structure-activity relationship update on our recently discovered novel hypotensive vasopressin peptides. Bioassays have been, and continue to be, of critical importance in leading to the discovery of the novel agonists, antagonists and hypotensive peptides reported here. This paper highlights three main aspects of these studies. (1) Replacement of the tyrosine' and/or phenylalanine3 residues in the V, agonist deamino,[Va14, ~-Arg~]arginine-vasopressin (dVDAVP) by thienylalanine resulted in selective V, agonists with strikingly high potencies. However, the peptide solutions were unstable and lost activity over time. These highly potent V, agonists, which are devoid of vasopressor activity, are promising leads for improving drugs for treating diabetes insipidus, enuresis and coagulation disorders. (2) (1895) injected an extract of the pituitary gland into an anaesthetised dog and found that the extract had a potent vasopressor activity. A decade later, Dale (1906) while studying the vasopressor action of the pituitary extract discovered that the extract also possessed a powerful stimulating action on Ihe smooth muscle of the uterus. These observations were the first experimental evidence that ultimately established the biological functions of the posterior pituitary gland and its hormones: vasopressin and oxytocin. The two historical findings were incidental discoveries uncovered during an exploration of the biological activities of pituitary extracts in intact whole animal experiments. The overriding theme of this review is the discovery of a series of novel, selective, hypotensive vasopressin peptides. Like the pioneering work noted above, the hypotensive activity of these vasopressin peptides was also discovered incidentally while we were carrying out bioassay characterisations on a series of newly designed vasopressin V, receptor antagonists aimed at developing more selective and potent V, receptor antagonists.Publication of The Physiological Society

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“…MDF-3 and -4 are composed of amino acid sequences that are not part of the feuin sequence and are also different from each other (Loeb and Jaffe, 2002). Such broad immunosensitivity may reflect similarities in the 3-dimensional configuration of the peptides or in flexibility that enables them to assume different topological configurations, thereby allowing conformation to the same antigen or receptor (Hruby, 1986). Double staining was realized in a minority of the cells in each group, implying that more than one peptide can be secreted or stored in some H. virescens midgut columnar cells.…”

Section: Discussionmentioning

confidence: 97%

Implications for the functions of the four known midgut differentiation factors: An immunohistologic study of Heliothis virescens midgut

Loeb¹,

Coronel²,

Natsukawa

et al. 2004

Arch Insect Biochem Physiol

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Antibodies to the peptides that induce differentiation of midgut larval stem cells, the midgut differentiating factors MDF-2, MDF-3, and MDF-4, bind to columnar cells in midgut cultures and in intact midgut of Heliothis virescens, in manners similar to the binding of anti- MDF-1 to those tissues. Antibodies to MDF-2 and MDF-3 also stained droplets in the midgut lumen, suggesting that columnar cells may also release MDF-2- and MDF-3-like cytokines to the lumen. Antibody to MDF-4 exhibited similar staining patterns but also recognized stem and differentiating cells, the presumed targets of peptides that regulate stem cell differentiation. Antibody to MDF-4 also bound to one type of endocrine cell in midgut cultures and in sections of midgut, as well as to the endocrine secretion released both to the midgut lumen and the hemolymph. Antibodies to the MDFs 1, 2, and 3, incubated with cultures of midgut cells, did not appear to prevent differentiation of the stem cells in the cultures but affected viability of mature cells, reflected in increased apoptosis and doubling of the number of differentiating cells compared to controls. Only antibody to MDF-4 induced temporary necrosis and inhibition of population recovery, indicating that MDF4 may be the true differentiation factor. The other MDFs may have additional functions beyond regulation of midgut stem cell differentiation in vivo.

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Structure–Activity of the Neurohypophyseal Hormones and Analogs and Implications for Hormone–Receptor Interactions

Cited by 12 publications

References 186 publications

Characterization of oxytocin receptors in rat adenohypophysis using a radioiodinated receptor antagonist peptide

Characterization of oxytocin receptors in rat adenohypophysis using a radioiodinated receptor antagonist peptide

Discovery and design of novel and selective vasopressin and oxytocin agonists and antagonists: the role of bioassays

Implications for the functions of the four known midgut differentiation factors: An immunohistologic study of Heliothis virescens midgut

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