Vasopressin synthesis

Logically, ADH receptor antagonists, and ADH synthesis and release inhibitors can be effective aquaretics. ADH, 8-arginine vasopressin [113-79-17, is synthesized in the hypothalamus of the brain, and is transported through the supraopticohypophyseal tract to the posterior pituitary where it is stored. Upon sensing an increase of plasma osmolaUty by brain osmoreceptors or a decrease of blood volume or blood pressure detected by the baroreceptors and volume receptors, ADH is released into the blood circulation it activates vasopressin receptors in blood vessels to raise blood pressure, and vasopressin V2 receptors of the nephrons of the kidney to retain water and electrolytes to expand the blood volume. 

Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) are members of a family of so-called natriuretic peptides, synthesized predominantly in the cardiac atrium, ventricle, and vascular endothelial cells, respectively (G13, Y2). ANP is a 28-amino-acid polypeptide hormone released into the circulation in response to atrial stretch (L3). ANP acts (Fig. 8) on the kidney to increase sodium excretion and glomerular filtration rate (GFR), to antagonize renal vasoconstriction, and to inhibit renin secretion (Ml). In the cardiovascular system, ANP antagonizes vasoconstriction and shifts fluid from the intravascular to the interstitial compartment (G14). In the adrenal cortex, ANP is a powerful inhibitor of aldosterone synthesis (E6, N3). At the hypothalamic level, ANP inhibits vasopressin secretion (S3). It has been shown that some of the effects of ANP are mediated via a newly discovered hormone, called adreno-medullin, controlling fluid and electrolyte homeostasis (S8). The diuretic and blood pressure-lowering effect of ANP may be partially due to adrenomedullin (V5). 

The vascular endothelium produces a number of substances that are released basally into the blood vessel wall to alter vascular smooth muscle tone. One such substance is endothelin (ET-1). Endothelin exerts its effects throughout the body, causing vasoconstriction as well as positive inotropic and chronotropic effects on the heart. The resulting increases in TPR and CO contribute to an increase in MAP. Synthesis of endothelin appears to be enhanced by many stimuli, including Ag II, vasopressin, and the mechanical stress of blood flow on the endothelium. Synthesis is inhibited by vasodilator substances such as prostacyclin, nitric oxide, and atrial natriuretic peptide. There is evidence that endothelin is involved with the pathophysiology of many cardiovascular diseases, including hypertension, heart failure, and myocardial infarction. Endothelin receptor antagonists are currently available for research use only. 

Rich, D.H., Gesellchen, P.D., Tong, A., Cheung, A., and Buckner, C.K. (1975) Alkylating derivatives of amino acids and peptides. Synthesis of N-maleoyl amino acids, l-[N-maleoylglycyl-cysteinyl]-oxytocin and l-[N-maleoyl-ll-aminoundecanoyl-cysteinyl]-oxytocin. Effects on vasopressin stimulated water loss from isolated toad bladder. J. Med. Chem. 18,1004-1010. 

This transmembrane signaling system involves a complex consisting of several functional proteins (Figure 7) stimulatory (e.g. P-adrenergic, dopamine Dp serotonin, vasopressin) [124] and inhibitory (e.g. a2-adrenergic, dopamine D2, opiod, and muscarinic) [125] receptors, stimulatory (Gs) and inhibitory (G ) G-proteins, and the catalytic protein, adenylate cyclase. On stimulation of a receptor, an associated G-protein binds GTP and the resulting receptor/G-protein/GTP complex then activates, or inhibits, adenylate cyclase in the catalysis of the synthesis... 

Li+ also inhibits several hormone-stimulated adenylate cyclases which, in some cases, appear to be related to side effects of Li+ therapy. For instance, Li+ inhibits the hydro-osmotic action of vasopressin, the antidiuretic hormone which increases water resorption in the kidney [136]. This effect is associated with polyuria, a relatively harmless side effect sometimes experienced with Li+ treatment, which arises from the inability of the kidney to concentrate urine. Li+ has been shown to inhibit vasopressin-stimulated adenylate cyclase activity in renal epithelial cells. Additionally, Li+ is reported to enhance the vasopressin-induced synthesis of prostaglandin E2 (PGE2) in vitro in kidney. PGE2 inhibits adenylate cyclase activity by stimulation of Gj, and, therefore, this effect may contribute to the Li+-induced polyuria. 

Recently, Curran described a procedure using triethylborane for the synthesis of spirooxindoles and spirodihydroquinolones through intramolecular addition of aryl radicals at the ipso position 4-alkoxy-substituted aromatic rings [15]. The key step for a formal synthesis of the vasopressin inhibitor SR121463A is described in Scheme 5. The initiation was performed with Et3B in an open to air reaction vessel. 

Scheme 5 Silane mediated key cyclization for a formal synthesis of the vasopressin inhibitor SR121463A...

Dantzer, R., and Bluthe, R.-M. 1992. Vasopressin involvement in antipyresis, social communication, and social recognition A synthesis. Critical Reviews in Neurobiology 16 243—255. 

Desmopressin Desmopressin, 8-D-arginine vasopressin-l-(3-mercaptopropionic acid) (24.4.6), is a structural analog of vasopressin. It is synthesized by a multi-step synthesis by methods specific to peptide chemistry, and its synthesis will not be examined here [71-74],... 

Fig. 2 Increased synthesis, content and release of vasopressin (AVP) in the PVN of high-anxiety (HAB) vs low-anxiety (LAB) rats under basal circumstances. Above left in situ hybridization. Above right immunocytochemistry (courtesy of Dr. N. Singewald, University of Innsbruck). Middle and below intra-PVN release of AVP and oxytocin (OXT) measured by in vivo microdialysis under basal conditions and in response to hypertonic stimulation to reveal the releasable neuropeptide pool. p<0.05, p<0.01 vs LAB. (Adapted from Wigger et al. 2004)...

Scheme 3 Synthesis of a Monocarba-vasopressin Analogue by the Solid-Phase Cyclization Method116 ...

The anterior lobe secretes various trophic hormones, the posterior lobe is responsible for the secretion of oxytocin and antidiuretic hormone (vasopressin) and middle lobe secretes melanocyte-stimulating hormone (MSH) which may affect the synthesis of melanin. 

Every hormone must have one or more receptors, most of which are proteins. These may be found embedded in the outer surface of the plasma membrane, in the cytoplasm, or in the cell nucleus. Binding of a hormone to its receptor often elicits both a rapid response and a slower one. For example, we have seen that glucagon, adrenaline, and vasopressin bind to cell surface receptors and promote the synthesis of cyclic AMP (Fig. 11-4). Tire cAMP induces rapid chemical modifications of many proteins. Some of these may diffuse into the nucleus and affect transcription of genes, a slower response. Insulin (Chapter 11, Section G) also exerts both rapid and slower responses. 

Vasopressin and oxytocin are peptide hormones secreted from the posterior lobe of the pituitary gland. They function primarily to raise blood pressure (vasopressin), as antidiuretic (vasopressin), and to promote contraction of uterus and lactation muscies (oxytocin). The isolation, identification, and synthesis of these hormones was accomplished by Vincent du Vigneaud, for which he was awarded the Nobel Prize in chemistry in 1955. 

NSAIDs inhibit prostaglandin synthesis. This can potentiate the effect of water reabsorption in the renal tubules of vasopressin. 

Enzymatic reactions now have a sound place in contemporary synthetic methodology. Illustrative of this, lipase-catalyzed transesterification of the racemic alcohol 65 has been used effectively to produce (6)-(+)-66 (LipaseQL, 0-5 °C, 4 h 47% yield >99% ee), plus the (R)-(—)-acetoxy derivative 67 (Equation 8). The 1-benzazepine derivative 66 was then converted to a chiral precursor required for the synthesis of the nonpeptide vasopressin V2 receptor agonist, OPC-51803 <2002H(58)635>. The synthesis of a 1-benzazepine-based antagonist (OPC-41061) at this receptor has also been reported <2002H(56)123>. 

Corticotropin-releasing factor and arginine vasopressin, which are released predominantly by the paraventricular nucleus of the hypothalamus, are important regulators of corticotropin (ACTH) release, which in turn triggers the release of cortisol and other steroids by the adrenal gland. Both the administration of certain psychoactive agents and emotional arousal originating from the limbic system are able to modify the functions of the pituitary-adrenal axis and stimulate the synthesis of cortisol. 

P Dreyfuss. Synthesis and some pharmacological properties of 8-e-hydroxy norleu-cine-vasopressin. J Med Chem 17 252-257, 1974. 

As Of 2009, conivaptan HCl (1) is one of three vasopressin receptor antagonists approved for use in the treatment of hyponatremia worldwide. The U.S. approval of 1 was preceded by the 2006 approval of mozavaptan hydrochloride (2) in Japan. In 2009, tolvaptan (3) joined 1 as an FDA-approved agent for the treatment of hyponatremia. In this chapter, the pharmacological profile and synthesis of conivaptan hydrochloride (1) is examined in detail. 

The actual site of formation of oxytocin and vasopressin is in the hypothalamus, from which the two peptides are carried to the posterior pituitary bound to neuro-physins (transport proteins) and stored. The structure and synthesis of oxytocin 44 and vasopressin 45 were worked out by du Vigneaud et al. 91... 

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