TY - JOUR T1 - Pharmacological Characterization of FE 202158, a Novel, Potent, Selective, and Short-Acting Peptidic Vasopressin V1a Receptor Full Agonist for the Treatment of Vasodilatory Hypotension JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.111.178848 SP - jpet.111.178848 AU - Regent Laporte AU - Arash Kohan AU - Joshua Heitzmann AU - Halina Wisniewska AU - Jeannine Toy AU - Erin La AU - Hiroe Tariga AU - Sudarkodi Alagarsamy AU - Brian Ly AU - John Dykert AU - Steve Qi AU - Kazimierz Wisniewski AU - Robert Galyean AU - Glenn Croston AU - Claudio D. Schteingart AU - Pierre J.-M. Riviere Y1 - 2011/01/01 UR - http://jpet.aspetjournals.org/content/early/2011/03/16/jpet.111.178848.abstract N2 - FE 202158, a peptidic analog of the vasoconstrictor hormone arginine vasopressin (AVP), was designed to be a potent, selective, and short-acting vasopressin type 1a receptor (V1aR) agonist. In functional reporter gene assays, FE 202158 was a potent and selective human V1aR agonist (EC50 = 2.4 nM; selectivity ratio of 1/142/1107/440 versus human V1bR, V2R, and OTR, respectively) contrasting with AVP's lack of selectivity, especially versus the V2R (selectivity ratio of 1/18/0.2/92; human V1aR EC50 = 0.24 nM). This activity and selectivity profile was confirmed in radioligand binding assays. FE 202158 was a potent vasoconstrictor in the isolated rat common iliac artery ex vivo (EC50 = 3.6 nM versus 0.8 nM for AVP) and reduced rat ear skin blood flow after intravenous infusion in vivo (ED50 = 4.0 pmol/kg/min vs 3.4 pmol/kg/min for AVP). The duration of its vasopressor effect by intravenous bolus in rats was as short as AVP at submaximally effective doses. FE 202158 had no V2R mediated antidiuretic activity in rats by intravenous infusion at its ED50 for reduction of ear skin blood flow, in contrast with the pronounced antidiuretic effect of AVP. Thus, FE 202158 appears suitable for treatment of conditions where V1aR activity is desirable but V2R activity is potentially deleterious, such as vasodilatory hypotension in septic shock. In addition to the desirable selectivity profile, its short-acting nature should allow dose titration with rapid onset and offset of action to optimize vasoconstriction efficacy and safety. ER -