Oxytocins

What Has This Got to Do with Oxytocin I Thought That Was All to Do with Pregnancy and Feeding Babies  

In humans, oxytocin is produced in the hypothalamus and released from the 

There are receptors in many parts of the brain, as well as elsewhere in the body, such as the reproductive system. In lactating mothers who are 

Breastfeeding releases oxytocin which helps bonding between baby and mother 

It has been used in maternity wards as the drug Pitocin, where it has been given to heavily pregnant women to induce labor, although it is not as effective as the natural release of oxytocin. It has now been found to have a role in the male reproductive system, too, being synthesized in the male testis, epididymis and prostate. 

The potent (IC50 = 8.9 nM, rat uterus 26 nM, human uterus), orally available (bioavailability 21% in three species) oxytocin antagonist L-368,899 is currently undergoing clinical evaluation. The authors are continuing their efforts to increase the understanding of the relationship between the nonpeptide and peptidic oxytocin antagonists. The aim of this work is to develop a pharmacophore model that will assist in the discovery of new structural classes of antagonists. 

The disulfide bridge between the two cysteine residues appears more realistically if the structure is drawn in the manner of organic chemists  

At the time of the conclusion of this study the elucidation of the structure of a nonapeptide was regarded as a major achievement. It could be realized only because of the advances made in the methodology of peptide research during the preceding years, for instance purification by Craig distribution or sequential degradation by the Edman method. The approach that yielded the even more complex structure of insuhn [13], namely partial acid hydrolysis followed by 

Reduction, S-benzylation, de-benzylation and oxydative recyclization of oxytoxin 

At this point it is interesting to note, that the method of reducing disulfides with sodium in liquid ammonia [16], benzylation of the thiol groups in situ and their debenzylation in the same solvent [17] had been elaborated by du Vigneaud many years earher (cf, p. 71) as if some intuition would have directed his efforts toward the chemistry of oxytocin. An account of this continued interest in sulfur containing natural products can be found in his book A Trail of Research [18]. 

In the existing know-how of the field of peptide synthesis only limited guidance could be found and designing a scheme for the synthesis of oxytocin was a major challenge. No similar undertaking had been published up till then. Peptides obtained by synthesis were either much smaller or of fairly simple amino acid composition. Yet, the partially blocked dipeptide N-benzyloxycarbonyl-5-benzyl-L-cysteinyl-L-tyrosine, the N-terminal sequence, had already been pre- 

Chemical Name A complex peptide see structural formula Common Name — 

Chemical Abstracts Registry No. 50-56-6 Trade Name Manufacturer 

Trade Name Manufacturer Country Year Introduced 

N-Ditrityl-L-cysteine diethylamine selt L-Tyrosine lower alkyl ester L-lsoleucine lower alkyl ester Benzyl-L-proline hydrochloride L-Leucine lower alkyl ester Ammonia Hydrogen chloride Glycine lower alkyl ester 

As described in U.S. Patent 2,938,891, in the process for producing oxytocin, the steps comprise  

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What protected ammo acid would you anchor to the solid support m the first step of a syn thesis of oxytocin (see Figure 27 8) by the Memfield method" ... 

The principal hormones of the human posterior pituitary include the two nonapeptides, oxytocin [50-56-6] and arginine vasopressin [11000-17-2] (antidiuretic hormone, ADH). Many other hormones, including opioid peptides (see Opioids, endogenous), cholecystokinin [9011-97-6] (CCK) (see Hormones, BRAIN oligopeptides), and gastrointestinal peptides, also have been located in mammalian neurohypophysis (6), but are usually found in much lower concentrations (7). Studies have demonstrated that oxytocin and vasopressin are synthesized in other human organs, both centrally and peripherally, and there is considerable evidence for their role as neurotransmitters (see Neuroregulators) (8). 

Fig. 1. Stmcture of oxytocin and arginine vasopressin. Numbers indicate approximate location of amino acids sequences found in Table 1. A, oxytocin B,...

Hundreds of analogues of both oxytocin and vasopressin have been synthesized, and the conformations of many of these have been studied (22,23). 

Table 2. Synthetic Analogues of Oxytocin with High Potency or Selectivity...

Table 4. Synthetic Analogues of Oxytocin and Vasopressin Having Antagonist Activities...

Oxytocin and Vasopressin Receptors. The actions of oxytocin and vasopressin are mediated through their interactions with receptors. Different receptor types as well as different second messenger responses help explain their diverse activities in spite of the hormones stmctural similarities. Thus oxytocin has at least one separate receptor and vasopressin has been shown to have two principal receptor types, and V2. Subclasses of these receptors have been demonstrated, and species differences further compHcate experimental analysis. It is apparent that both oxytocin and receptors function through the GP/1 phosphoHpase C complex (75), while the V2 receptors activate cycHc AMP (76). 

Several human receptors for the neurohypophyseal hormones have been cloned and the sequences elucidated. The human V2 receptor for antidiuretic hormone presumably contains 371 amino acids and seven transmembrane segments and activates cycHc AMP (76). The oxytocin receptor is a classic G-protein-coupled type of receptor with a proposed membrane topography also involving seven transmembrane components (84). A schematic representation of the oxytocin receptor stmcture within the membrane is shown in Eigure 4 (85). 

Fig. 4. Representation of proposed topography of human oxytocin receptor (85) where CHO represents carbohydrate.

D. Ganttei and D. Pfaff, eds., Neurohiology of Oxytocin, Spriagei-Vedag, Berha, 1986. 

Disulfides. As shown in Figure 4, the and h-chains of insulin are connected by two disulfide bridges and there is an intrachain cycHc disulfide link on the -chain (see Insulin and other antidiabetic drugs). Vasopressin [9034-50-8] and oxytocin [50-56-6] also contain disulfide links (48). Oxidation of thiols to disulfides and reduction of the latter back to thiols are quite common and important in biological systems, eg, cysteine to cystine or reduced Hpoic acid to oxidized Hpoic acid. Many enzymes depend on free SH groups for activation—deactivation reactions. The oxidation—reduction of glutathione (Glu-Cys-Gly) depends on the sulfhydryl group from cysteine. 

Vasopressin and Oxytocin. Arginine -vasopressin (AVP, vasopressia also known as antidiuretic hormone, ADH) (342) is a nonapeptide amide that functions both as a neuroregulator and a hormone (84,85). Oxytocia (OT) (343) is a nonapeptide amide related to AVP. 

Table 20. Vasopressin and Oxytocin and Receptor Agonists and Antagonists...

OT receptors are localized ia the brain hypothalamus, limbic system, cortex, striatum, olfactory system, and brain stem. In the periphery, OT is best known for its stimulation of uterine smooth muscle and the milk ejection reflex. Thr , Om ]oxytocin(l—8),... 

Oxytocin [50-56-6] M 1007.2, m dec on heating, [a] -26.2"(c 0.53, N AcOH). A cyclic nonapeptide which was purified by countercurrent distribution between solvent and buffer. It is soluble in H2O, rt-BuOH and isoBuOH. [Bodanszky and du Vigneaud J Am Chem Soc 81 2504 1959 Cash et al. J Med Pharm Chem 5 413 1962 Sakakibara et al. Bull Chem Soc Jpn 38 120 1965 solid phase synthesis Bayer and... 

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