I [increasing lipophilicity]
" Reproduced in part from J. B. Lee, in "Principles of Endocrinology" (R. H. Williams, ed.) 5th ed., p 855. Saunders, Philadelphia, Pennsylvania, 1975.
series (PGA) is the least polar or hydrophilic, is the most lipophilic, and has no hydroxyl groups substituted on the five-membered ring, but rather a ketone group and an unsaturation (Table 16-1). These classes of PGs have characteristic actions depending on the five-membered-ring substituents, as shown in Table 16-1.
Inspection of Table 16-1 provides an easy means to relate structure with activity. Since PGF is the most water-soluble, it has hydroxyl groups on both C-9 and C-ll. As will be seen later, PGF plays a role in the termination of pregnancy. This association will make
FIGURE 16-3 Routes of synthesis to some of the PGs, PGI2, TX, LT, and LP from arachidonic acid. Note that all of the classes of PG relatives are synthesized through a cyclic endoperoxide intermediate except for the LTs and LPs and related structures, which are essentially modified fatty acids. A major activity of cyclooxygenase (COX2) is inducing inflammation and is repressed by glucocorticoids at the transcriptional level. Nonsteroidal anti-inflammatory drugs (aspirin and indomethacin) inhibit COX2 by transacetylation of the catalytic center of the enzyme. Whereas steroids should also shut down LT and LP formation in addition to PG (COX inhibition) by inhibition of phospholipase A2 mediated by induction of lipocortin/ annexin I, nonsteroidal drugs (NSAID) are not expected to affect LT and LP since they operate mainly on COX.
it possible to remember that the F series is active in muscular contraction (i.e., as in uterine contractions of parturition).
The PGE series is intermediate between PGF and PGA. Consequently, it shares both activities of those groups as well as their characteristic ring substituents. The structure, therefore, can be deduced as one in which the ring has both a hydroxyl (typical of PGF) and a ketone (typical of PGA) and has the activities of both stimulating muscular contraction and decreasing blood pressure. Finally, PGA is the least polar (a ketone and a double bond in the ring) and has activity opposite that of PGF; it reduces blood pressure and has little effect on nonvascular muscle contraction.
In designating the PGs, two kinds of subscripts may appear at the end of the abbreviation (e.g., PGF2„). The subscript, which is a number, denotes the number of double bonds in the structure. The Greek letter, a, following the subscript number refers to the steric position of the C-9 substituent (a indicates extension behind the plane of the ring, away from the reader). This becomes apparent in the structure of PGF,„. If 2 is added to this number (4 in the case of PGF2a), we get the number of double bonds that must have been present in the fatty acid precursor of PGF2a, that is, eicosatetraenoic acid (20:4«6) or arachidonic acid. The information in parentheses, in this case (20:4cu6), presents information about the fatty acid. Thus, 20 is the number of carbons in the structure, 4 is the number of double bonds, and co6 indicates that there are six methyls in the chain from the end until a double bond appears (Figure 16-4).
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