New, Potent, Selective, and Short-Acting Peptidic V_1a Receptor Agonists

Abstract

[Arg(8)]vasopressin (AVP) produces vasoconstriction via V(1a) receptor (V(1a)R)-mediated vascular smooth muscle cell contraction and is being used to increase blood pressure in septic shock, a form of vasodilatory hypotension. However, AVP also induces V(2) receptor (V(2)R)-mediated antidiuresis, vasodilation, and coagulation factor release, all deleterious in septic shock. The V(1a)R agonist terlipressin (H-Gly(3)[Lys(8)]VP) also lacks selectivity vs the V(2)R and has sizably longer duration of action than AVP, preventing rapid titration of its vasopressor effect in the clinic. We designed and synthesized new short acting V(1a)R selective analogues of general structure [Xaa(2),Ile(3),Yaa(4),Zaa(8)]VP. The most potent and selective compounds in in vitro functional assays (e.g., [Phe(2),Ile(3),Asn(Me(2))(4),Orn(8)]VP (31), [Phe(2),Ile(3),Asn((CH(2))(3)OH)(4),Orn(8)]VP (34), [Phe(2),Ile(3),Hgn(4),Orn(iPr)(8)]VP (45), [Phe(2),Ile(3),Asn(Et)(4),Dab(8)]VP (49), [Thi(2),Ile(3),Orn(iPr)(8)]VP (59), [Cha(2),Ile(3),Asn(4),Orn(iPr)(8)]VP (68)) were tested by intravenous bolus in rats for duration of vasopressive action. Analogues 31, 34, 45, and 49 were as short-acting as AVP. Compound 45, FE 202158, is currently undergoing clinical trials in septic shock.

Selective V1aagonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis

“…The maximum dose was based on a study of Torgersen et al (47) who reported the safety of AVP doses up to 0.067 units/min in patients with septic shock. Because POV has a similar potency (EC 50 ) as AVP at the human V 1a receptor (28,54), infusion preparations had the same concentrations. However, the selectivity of POV for the V 1a -versus the V 2 receptor is more than 220 times higher than AVP, thus resulting in a lack of V 2 -receptor activity (2).…”

“…Another potential limitation is the lack of dose response studies in the present sepsis model. However, appropriate pharmacological studies with POV and AVP have been published recently (54).…”

In Vitro Evaluation of New, Potent and Selective V2 Receptor Agonists

“…1 was particularly selective vs. the V1aR (>1000-fold) presumably due to the desamino modification [6]. The Val 4 analogue of 1 ([Val 4 ]dDAVP, 2) has been reported to be more potent and selective than 1 in rat in vivo models [7].…”

Macrocyclic Inhibitors of GPCR's, Integrins and Protein–Protein Interactions

“…158 The treatment of vasodilatory hypotension as observed in septic shock would however require a V 1a R-selective agonist with a short half-life. 159 The synthesis of analogs of AVP modified in positions 2, 3, 4, and 8 afforded a series of compounds with a suitable profile, among them 80 (FE202158, Figure 8.29), 158 which was found to be a potent and selective full agonist at the human V 1a receptor (Table 8.5) and also a potent vasoconstrictor in vivo in rats, as shown by dose-dependent reduction of ear skin blood flow (ED 50 of 4.0 pmol kg À1 min À1 ; given by constant intravenous infusion), with no V 2 R mediated antidiuretic activity. 159 Macrocycle 80 (FE202158) was chosen for clinical trials for the treatment of septic shock.…”