1-O-alkyl-2-N-methylcarbamyl-glycerophosphocholine: a biologically potent, non-metabolizable analog of platelet-activating factor.
We prepared unlabeled and 3H-labeled analogs of platelet-activating factor (PAF) containing a N-methylcarbamyl residue at the sn-2 position. PAF and its methylcarbamyl analog competed for binding to high affinity receptors on human polymorphonuclear neutrophils; their respective dissociation constants for these receptors were 0.2 and 1.1 nM. The binding affinities of the two analogs correlated precisely with their capacities to stimulate neutrophil degranulation responses. Unlike PAF, however, the methylcarbamyl analog completely resisted metabolic inactivation by neutrophils and by human sera. Thus, these compounds' biological potencies are determined predominantly by receptor binding: cellular metabolism of the ligands neither contributes to nor appreciably limits their stimulating actions.
O'Flaherty
J T
JT
Redman
J F
JF
Schmitt
J D
JD
Ellis
J M
JM
Surles
J R
JR
Marx
M H
MH
Piantadosi
C
C
Wykle
R L
RL
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor / Q000031:analogs & derivatives* / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C053479:1-O-hexadecyl-2-N-methylcarbamylphosphatidylcholine; D007975:Leukotriene B4; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase