however, correlation of these values with the activation of adenylate cyclase is not very
convincing. Prostaglandin receptors have also been found in plasma membranes of the
corpus luteum, with a KDof 5–8 × 10 −^8 M. There are at least nine known prostaglandin
receptor forms, as well as several additional splice variants. The prostaglandin receptors
belong to three clusters (on the basis of homology) within a particular subfamily of the
G-protein receptor superfamily of seven transmembrane spanning proteins.
8.5.1.4 Prostaglandins: Structure–Activity Relationships
Studies of the structure–activity correlations and synthetic modifications of prostaglandins
and thromboxane are extremely active fields. Although a large number of analogs have
been synthesized, pharmacological information on these analogs is still unfolding.
Expansion or contraction of the cyclopentane ring or its replacement by heteroaro-
matic rings provides less active compounds in the E 2 and F 2 series. The replacement of
the ring oxygen in prostacyclin gives more stable analogs, which show about half of the
platelet aggregation-inhibiting effect of PGI 2 but act as a vasoconstrictor instead of a
vasodilator. Analogs containing a nitrogen atom at the same position are very stable and
good mimics of PGI 2.
The carboxylic acid side chain has also been modified extensively. The phenoxy
derivative is 10 times more active than PGE as an inhibitor of platelet aggregation, but
is a weak smooth-muscle spasmogen. The sulfonamide is 10–30 times more active than
PGE 2 as an antifertility agent, and has few side effects. This compound has also under-
goneco-chain (carbinol chain) modification. Successful derivatives were mainly found
among the 15- and 16-methyl PGE 2 analogs: carboprost (8.67) possesses very high
uterotonic activity and is used to induce abortions. They probably inhibit the dehydrase
that inactivates the prostaglandins by removing the 15-OH group. Misoprostol (8.68)is
a modified prostaglandin analog that shows potent gastric antisecretory and gastro-
protective effects. It has been used to treat and prevent gastric ulcers.
8.5.2 Anti-Prostaglandins as Anti-Inflammatory
Agents and Minor AnalgesicsAnti-inflammatory agents are believed to act by disrupting the arachidonic acid cascade.
These drugs are widely used for the treatment of minor pain and arthritis. Some of them
are antipyretics (drugs that reduce fever) in addition to having analgesic and anti-
inflammatory actions. Some of these agents are widely available in over-the-counter
(OTC) preparations. Collectively, these are referred to as nonsteroidal anti-inflammatory
drugs(NSAIDs). They may be classified as follows:
524 MEDICINAL CHEMISTRY