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Chapter: Basic & Clinical Pharmacology : Vasoactive Peptides

Vasopressin Receptors & Antagonists

Three subtypes of AVP receptors have been identified; all are G protein-coupled.


Three subtypes of AVP receptors have been identified; all are G protein-coupled. V1areceptors mediate the vasoconstrictor action of AVP; V1breceptors mediate release of ACTH by pituitary cortico-tropes; and V2receptors mediate the antidiuretic action. V1a effects are mediated by Gq activation of phospholipase C, formation of inositol trisphosphate, and increased intracellular calcium concentra-tion. V2 effects are mediated by Gs activation of adenylyl cyclase.

AVP analogs selective for vasoconstrictor or antidiuretic activ-ity have been synthesized. The most specific V1 vasoconstrictor agonist synthesized to date is [Phe2, Ile3, Orn8]vasotocin. Selective V2 antidiuretic analogs include 1-deamino[D-Arg8]arginine vaso-pressin (dDAVP) and 1-deamino[Val4,D-Arg8]arginine vasopres-sin (dVDAVP).

AVP has proved beneficial in the treatment of vasodilatory shock states, at least in part by virtue of its V1a agonist activity. Terlipressin (triglycyl lysine vasopressin), a synthetic vasopressinanalog that is converted to lysine vasopressin in the body, is also effective. It may have advantages over AVP because it is more selective for V1 receptors and has a longer half-life.

Antagonists of the vasoconstrictor action of AVP are also avail-able. The peptide antagonist d(CH2)5[Tyr(Me)2]AVP also has antioxytocic activity but does not antagonize the antidiuretic action of AVP. A related antagonist d(CH2)5[Tyr(Me)2,Dab5]AVP lacks oxytocin antagonism but has less anti-V1 activity. Recently, nonpeptide, orally active V1a-receptor antagonists have been dis-covered, examples being relcovaptan and SRX251.

The V1a antagonists have been particularly useful in revealing the important role that AVP plays in blood pressure regulation in situ-ations such as dehydration and hemorrhage. They have potential as therapeutic agents for the treatment of such diverse diseases and conditions as Raynaud’s disease, hypertension, heart failure, brain edema, motion sickness, cancer, preterm labor, and anger reduction. To date, most studies have focused on heart failure; promising results have been obtained with V2 antagonists such as tolvaptan, which is, however, currently approved only for use in hyponatremia. V1a antagonists also have potential, and conivaptan (YM087), a drug with both V1a and V2 antagonist activity, has also been approved for treatment of hyponatremia .

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Basic & Clinical Pharmacology : Vasoactive Peptides : Vasopressin Receptors & Antagonists |

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