20-hydroxyeicosatetraenoic acid (20-HETE): structural determinants for renal vasoconstriction.
The effects of natural and synthetic eicosanoids on the diameter of rat interlobular arteries studied in vitro were compared to that of the potent, endogenous vasoconstrictor 20-HETE. Vasoconstrictor activity was optimum for chain lengths of 20-22 carbons with at least one olefin or epoxide between located between C(13)-C(15) and an oxygen substituent at C(20)-C(22). The presence of delta (Zou et al. Am. J. Physiol. 1996, 270, R228; Gebremedhin, D. et al. Am. J. Physiol. 1998, 507, 771)-, delta (Carroll et al. Am. J. Physiol. 1996, 271, R863; Vazquez et al. Life Sci. 1995, 56, 1455)-, or delta (Imig et al. Hypertension 2000, 35, 307; Lopez et al. Amer. J. Physiol. 2001, 281, F420)-olefins had no influence on the vasoconstrictor response whereas the introduction of a C(7)-thiomethylene enhanced potency. A sulfonamide or alcohol, but not a lactone, could replace the C(1)-carboxylate. These data were used to construct a putative binding domain map of the 20-HETE receptor consisting of: (i) a comparatively open, hydrophilic binding site accommodating the C(1)-functionality; (ii) a hydrophobic trough spanning the olefins; (iii) a shallow pocket containing a critical pi-pi binding site in the vicinity of the pi (Ito et al. Am. J. Physiol. 1998, 274, F395; Quigley, R.; Baum, M.; Reddy, K. M.; Griener, J. C.; Falck, J. R. Am. J. Physiol. 2000, 278, F949)-olefin; and (iv) an oxyphilic binding site proximate to the omega-terminus.
Yu
Ming
M
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Alonso-Galicia
Magdalena
M
Sun
Cheng-Wen
CW
Roman
Richard J
RJ
Ono
Naoya
N
Hirano
Hitomi
H
Ishimoto
Tsuyoshi
T
Reddy
Y Krishna
YK
Katipally
Kishta Reddy
KR
Reddy
Komandla Malla
KM
Gopal
V Raj
VR
Yu
Ji
J
Takhi
Mohamed
M
Falck
J R
JR
D000818:Animals; D001665:Binding Sites; D006893:Hydroxyeicosatetraenoic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D007668:Kidney / Q000098:blood supply; D009682:Magnetic Resonance Spectroscopy; D051381:Rats; D018055:Receptors, Eicosanoid / Q000737:chemistry; D013329:Structure-Activity Relationship; D014661:Vasoconstriction / Q000187:drug effects*
D006893:Hydroxyeicosatetraenoic Acids; D018055:Receptors, Eicosanoid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid