Discovery of Potent, Selective, and Short-Acting Peptidic V Receptor Agonists.

The vasopressin analogue desmopressin (desamino-d-arginine vasopressin, dDAVP, 1) is a potent vasopressin 2 (V) receptor (VR) agonist approved in many countries for the treatment of diabetes insipidus, primary nocturnal enuresis, nocturia, and coagulation disorders. Since 1 is primarily excreted via the kidneys, an age-related decline in kidney function leads to slower elimination, prolonged antidiuresis, and hyponatremia. In search of novel, potent, selective, and short-acting peptidic VR agonists, we synthesized a series of C-terminally truncated analogues of [Val]dDAVP, 2, modified in positions 2, 3, and 7 and/or at the disulfide bridge.

Unlike arginine vasopressin, the selective V1a receptor agonist FE 202158 does not cause procoagulant effects by releasing von Willebrand factor.

Objective: To compare the effects on von Willebrand factor release of the mixed vasopressin type 1a and type 2 receptor agonist arginine vasopressin and the selective vasopressin type 1a receptor agonist FE 202158, [Phe2,Ile3,Hgn4,Orn(iPr)8]vasopressin, at doses required for the treatment of septic shock.

Design: Prospective, randomized, controlled laboratory experiment.

Setting: University animal research facility.

Pharmacological characterization of FE 202158, a novel, potent, selective, and short-acting peptidic vasopressin V1a receptor full agonist for the treatment of vasodilatory hypotension.

FE 202158, ([Phe(2),Ile(3),Hgn(4),Orn(iPr)(8)]vasopressin, where Hgn is homoglutamine and iPr is isopropyl), a peptidic analog of the vasoconstrictor hormone [Arg(8)]vasopressin (AVP), was designed to be a potent, selective, and short-acting vasopressin type 1a receptor (V(1a)R) agonist. In functional reporter gene assays, FE 202158 was a potent and selective human V(1a)R agonist [EC(50) = 2.4 nM; selectivity ratio of 1:142:1107:440 versus human vasopressin type 1b receptor, vasopressin type 2 receptor (V(2)R), and oxytocin receptor, respectively] contrasting with AVP's lack of selectivity, especially versus the V(2)R (selectivity ratio of 1:18:0.