Replacement of the carboxylic acid group of prostaglandin f(2alpha) with a hydroxyl or methoxy substituent provides biologically unique compounds.
Replacement of the carboxylic acid group of PGF(2alpha) with the non-acidic substituents hydroxyl (-OH) or methoxy (-OCH(3)) resulted in an unexpected activity profile. Although PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) exhibited potent contractile effects similar to 17-phenyl PGF(2alpha) in the cat lung parenchymal preparation, they were approximately 1000 times less potent than 17-phenyl PGF(2alpha) in stimulating recombinant feline and human FP receptors. In human dermal fibroblasts and Swiss 3T3 cells PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) produced no Ca(2+) signal until a 1 microM concentration was exceeded. Pretreatment of Swiss 3T3 cells with either 1 microM PGF(2alpha) 1-OH or PGF(2alpha) 1-OCH(3) did not attenuate Ca(2+) signal responses produced by PGF(2alpha) or fluprostenol. In the rat uterus, PGF(2alpha) 1-OH was about two orders of magnitude less potent than 17-phenyl PGF(2alpha) whereas PGF(2alpha) 1-OCH(3) produced only a minimal effect. Radioligand binding studies on cat lung parenchymal plasma membrane preparations suggested that the cat lung parenchyma does not contain a homogeneous population of receptors that equally respond to PGF(2alpha)1-OH, PGF(2alpha)1-OCH(3), and classical FP receptor agonists. Studies on smooth muscle preparations and cells containing DP, EP(1), EP(2), EP(3), EP(4), IP, and TP receptors indicated that the activity of PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) could not be ascribed to interaction with these receptors. The potent effects of PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) on the cat lung parenchyma are difficult to describe in terms of interaction with the FP or any other known prostanoid receptor.
Woodward
D F
DF
Department of Biological Sciences, Allergan, Inc., Irvine, California, USA.
Krauss
A H
AH
Chen
J
J
Gil
D W
DW
Kedzie
K M
KM
Protzman
C E
CE
Shi
L
L
Chen
R
R
Krauss
H A
HA
Bogardus
A
A
Dinh
H T
HT
Wheeler
L A
LA
Andrews
S W
SW
Burk
R M
RM
Gac
T
T
Roof
M B
MB
Garst
M E
ME
Kaplan
L J
LJ
Sachs
G
G
Pierce
K L
KL
Regan
J W
JW
Ross
R A
RA
Chan
M F
MF
D016475:3T3 Cells; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D002415:Cats; D002460:Cell Line; D004274:DNA, Recombinant; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D015230:Prostaglandin D2 / Q000378:metabolism; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D017482:Receptors, Thromboxane / Q000378:metabolism; D013329:Structure-Activity Relationship
D004274:DNA, Recombinant; C545635:PTGER1 protein, human; C545644:PTGER2 protein, human; C545647:PTGER3 protein, human; C545650:PTGER4 protein, human; C113936:PTGIR protein, human; D011461:Prostaglandins F, Synthetic; C545636:Ptger1 protein, mouse; C545637:Ptger1 protein, rat; C545645:Ptger2 protein, mouse; C545646:Ptger2 protein, rat; C545648:Ptger3 protein, mouse; C545649:Ptger3 protein, rat; C545651:Ptger4 protein, mouse; C545652:Ptger4 protein, rat; C491910:Ptgir protein, mouse; C491909:Ptgir protein, rat; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D017482:Receptors, Thromboxane; C034671:prostaglandin F2alpha receptor; C006326:fluprostenol; C027042:17-phenylprostaglandin F2alpha; D015237:Dinoprost; D015230:Prostaglandin D2; D002118:Calcium