title: Pharmacological characterization of FE 202158, a novel, potent, selective, and short-acting peptidic vasopressin V1a receptor full agonist for the treatment of vasodilatory hypotension.
abstract: 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 1:18:0.2:92; human V(1a)R EC(50) = 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 (EC(50) = 3.6 nM versus 0.8 nM for AVP) and reduced rat ear skin blood flow after intravenous infusion in vivo (ED(50) = 4.0 versus 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 V(2)R-mediated antidiuretic activity in rats by intravenous infusion at its ED(50) for reduction of ear skin blood flow, in contrast with the pronounced antidiuretic effect of AVP. Thus, FE 202158 seems suitable for treatment of conditions where V(1a)R activity is desirable but V(2)R 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.
authors.affiliation: Ferring Research Institute, Inc., 4245 Sorrento Valley Boulevard, San Diego, CA 92121, USA. regent.laporte@ferring.com
authors.forename: Régent
authors.initials: R
authors.lastname: Laporte
authors.forename: Arash
authors.initials: A
authors.lastname: Kohan
authors.forename: Joshua
authors.initials: J
authors.lastname: Heitzmann
authors.forename: Halina
authors.initials: H
authors.lastname: Wisniewska
authors.forename: Jeannine
authors.initials: J
authors.lastname: Toy
authors.forename: Erin
authors.initials: E
authors.lastname: La
authors.forename: Hiroe
authors.initials: H
authors.lastname: Tariga
authors.forename: Sudarkodi
authors.initials: S
authors.lastname: Alagarsamy
authors.forename: Brian
authors.initials: B
authors.lastname: Ly
authors.forename: John
authors.initials: J
authors.lastname: Dykert
authors.forename: Steve
authors.initials: S
authors.lastname: Qi
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Wisniewski
authors.forename: Robert
authors.initials: R
authors.lastname: Galyean
authors.forename: Glenn
authors.initials: G
authors.lastname: Croston
authors.forename: Claudio D
authors.initials: CD
authors.lastname: Schteingart
authors.forename: Pierre J-M
authors.initials: PJ
authors.lastname: Rivière
mesh_terms: D000818:Animals; D050034:Antidiuretic Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D001127:Arginine Vasopressin / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D006801:Humans; D007022:Hypotension / Q000188:drug therapy*; D008297:Male; D058990:Molecular Targeted Therapy; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D018045:Receptors, Oxytocin / Q000819:agonists / Q000378:metabolism; D017483:Receptors, Vasopressin / Q000819:agonists* / Q000378:metabolism; D013997:Time Factors; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D014667:Vasopressins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D050034:Antidiuretic Agents; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; D014662:Vasoconstrictor Agents; C559490:vasopressin, Phe(2)-Ile(3)-Hgn(4)-Orn(iPr)(8)-; D014667:Vasopressins; D001127:Arginine Vasopressin