Abstract
FE 202158, ([Phe2,Ile3,Hgn4,Orn(iPr)8]vasopressin, where Hgn is homoglutamine and iPr is isopropyl), a peptidic analog of the vasoconstrictor hormone [Arg8]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 vasopressin type 1b receptor, vasopressin type 2 receptor (V2R), and oxytocin receptor, 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 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 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 seems 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.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.178848.
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ABBREVIATIONS:
- AVP
- [Arg8]vasopressin
- CI
- confidence interval
- CCRC
- cumulative concentration-response curves
- CH2O
- free water clearance
- CHO
- Chinese hamster ovary
- DAP
- diastolic arterial pressure
- Emax
- maximal possible response produced by an agonist or an antagonist
- EWC
- effective water clearance
- Hgn
- homoglutamine
- Hmp
- 2-hydroxy-3-mercaptopropionic acid
- F-180
- [Hmp1,Phe2,Hgn4,Dbu(Abu)8]vasotocin
- iPr
- isopropyl
- FE 202158
- [Phe2,Ile3,Hgn4,Orn(iPr)8]vasopressin
- HEK
- human embryonic kidney
- Luc
- luciferase
- NFAT
- nuclear factor of activated T cells
- nH
- Hill coefficient
- OT
- oxytocin
- OTR
- OT receptor
- pA2
- negative logarithm of the concentration of antagonist needed to shift the CCRC by a factor of 2
- PSS
- physiological salt solution
- Uosm
- urine osmolality
- V1aR
- vasopressin type 1a receptor
- V1bR
- vasopressin type 1b receptor
- V2R
- vasopressin type 2 receptor
- U.S.P.
- United States Pharmacopeia
- U-50488
- 2-(3,4-dichlorophenyl)-N-methyl-N-[(1R,2R)-2-pyrrolidin-1-ylcyclohexyl]acetamide
- Pmp
- β,β-cyclopentamethylene-β-mercaptopropionyl.
- Received January 6, 2011.
- Accepted March 14, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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