Definition
Vasotocin analog 1–deamino[8–lysine(Ne–4–azidobenzoyl)] vasotocin ([Mpa1, Lys(Ne–4–azidobenzoyl)8]vasotocin) are useful for the isolation of vasotocin receptors in low vertebrates and oxytocin receptors in mammals.
Discovery
Cheesman DW et al., in 1983 synthesized a series of analogs of arginine vasotocin by systematically substituting each residue, and then evaluated the anovulatory activity of these compounds in the rat, investigating the correlation between molecular structure and anovulatory, pressor, and antidiuretic activities. Substitution of the N-terminus cysteine with 3-mercaptopropanoic acid in arginine vasotocin and arginine vasopressin produced a 3- to 4-fold increase in both anovulatory and antidiuretic activity and only a 10% change in pressor activity 1.
Structural Characteristics
Study describes the synthesis and biological activities of the photoreactive vasotocin analog 1–deamino[8–lysine(Ne–4–azidobenzoyl)] vasotocin ([Mpa1, Lys(Ne–4–azidobenzoyl)8]vasotocin). The analog was obtained by introducing the photoreactive aryl azido group at the e–amino group of Lys8 in [Mpa1, Lys8]-vasotocin, which was synthesized by the solid phase method 2. (Lys8)-Vasotocin (free acid) sequence is H-Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Lys-Gly-OH and sequence of (d(CH2)51,Tyr(Me)2,Thr4,Orn8,Tyr-NH29)-Vasotocin is β-Mercapto-β,β-cyclopentamethylene-propionyl-Tyr(Me)-Ile-Thr-Asn-Cys-Pro-Orn-Tyr-NH2 3.
Solid phase methodology on benzhydrylamine resin with linkage agent and Fmoc technique was used for the synthesis of two analogs of deamino carba-1 and carba-6 oxytocin with phenylalanine in position 2 and with ornithine in position 8. The following analogs were prepared: [Phe 2,Orn8]deamino-carba-1-oxytocin and [Phe2,Orn8]deamino-carba-6-oxytocin (II). Moreover, analogs with δ-amino group of ornithine protected by benzyloxycarbonyl group and its corresponding sulfoxides were isolated and tested 4.
Mode of Action
Experiments on rats showed that the intramuscular injections of arginine-vasotocin (AVT), 1-deamino-arginine-vasotocin (1dAVT) or 1-deamino-1-monocarba-arginine-vasotocin (1dlmcAVT) at a dose of 5 x 10(-11) mole per 100 g body weight increase renal excretion of Na+, K+, and Mg2+. Antagonist of V1 receptors (OPC-21268) decreases the effect of 1dAVT nonapeptides on renal excretion of the studied ions. A model of VIb-receptor is constructed and a correlation is shown between the energy of interaction of the V1b-receptor and the natriuretic effect of the studied vasotocin analogs 5.
In the isolated toad urinary bladder the photoaffinity analog of vasotocin retained hydroosmotic activity in the absence of UV-light. After irradiation the osmotic water flow across the bladder wall increased. Moreover, the water permeability remained high during repeated periods of washout, suggesting that the analog formed covalent complexes with vasotocin receptors in the toad bladder. In the rat uterotonic assay the photoreactive vasotocin analog was without photoactivation a mild agonist. These studies suggest that the photoaffinity analog of vasotocin might be useful for the isolation of vasotocin receptors in low vertebrates and oxytocin receptors in mammals 2.
Functions
Anovulatory activity, substitution of this cysteine in arginine vasotocin with 2-hydroxy-3-mercaptopropanoic acid produced an analog more potent in anovulatory activity than arginine vasotocin but less potent than [1-(3-mercaptopropanoic acid)]- arginine vasotocin. The most potent anovulatory analog synthesized was [1-(3-mercaptopropanoic acid)]-8-ornithine vasotocin, which gave a 10-fold increase in anovulatory activity, a 4-fold reduction in antidiuretic activity, and only a 10% increase in pressor potency when compared with arginine vasotocin 1.
Singing behavior, in early autumn the vasotocin analog enhanced song duration of testosterone-primed canaries, but the same vasotocin analog decreased song duration in the period November/January. These results suggest that the neuropeptide VT is implicated in control of seasonal changes in singing behavior 6.
Uterine receptor, the substitution of glutamine by threonine in position 4 of oxytocin, deamino-oxytocin, deamino-1-carba-oxytocin, and deamino-6-carba-oxytocin was found to increase the elimination rate of all analogs examined from the uterine receptor compartment in rat. However, this substitution was without any effect on the time course of uterotonic response in the case of vasotocin and deamino-vasotocin. These results suggest that the topological relationships of the 4 and 8 positions may show an important effect on elimination rate of oxytocin and vasotocin analogs from the rat uterine compartment 7.
References
1. Cheesman DW, Schlegel R, Sagasay AM, Forsham PH (1983). Anovulatory effect of synthetic analogs of arginine vasotocin in the rat. Endocrinology, 112:1269-1276.
2. Fahrenholz F, Eggena P, Kojro E, Gazis D, Schwartz IL (1987). Synthesis and biological activities of a photoaffinity probe for vasotocin and oxytocin receptors. Int J Pept Protein Res., 30(5):577-582.
3. Manning M, Sawyer WH (1989). Discovery, development, and some uses of vasopressin and oxytocin antagonists. J. Lab. Clin. Med., 114(6):617-632.
4. Procházka Z (2009). Deamino-Carba Analogs of Vasotocin. Synthesis and Some Biological Properties. Collection of Czechoslovak Chemical Communications, 59(2): 421-428.
5. Natochin IuV, Kanashkina TA, Shakhmatova EI, Bespalova ZhD, Mordvintsev DIu, Poliak IaL (2008). Effects of vasotocin analogs on excretion of Na+, K+, and Mg2+ ions via rat kidney. Eksp Klin Farmakol., 71(2):32-35.
6. Voorhuis TA, De Kloet ER, De Wied D (1991). Effect of a vasotocin analog on singing behavior in the canary. Horm Behav., 25(4):549-559.
7. Barth T, Slaninová J, Lebl M, Hruby VJ (1987). Effect of threonine in position 4 in oxytocin and vasotocin analogs on the time course of uterotonic response. Endocrinol-Exp., 21(3):191-197.