PROSTAGLANDIN A USEFUL STRATEGY FOR NEW DRUG DEVELOPMENT: A REVIEW

ABOUT AUTHORS:
S.P.Sethy*¹, P.Mishra², T.Sameena¹, P.Patil¹, K.Shailaja¹
*¹Department Of Pharmaceutical Chemistry, Sushrut Institute of pharmacy
Taddanpally (V), Pulkal (M), Medak Dist-502273
²Department Of Pharmacology.
Malla Reddy College Of Pharmacy, Maisamaguga,
Dhulapalli, Secunderabad-14
sarada9439504350@gmail.com

ABSTRACT:
The prostaglandins are a family of lipids, originally discovered over 30 years ago in human seminal fluid, which have since been found not only to have a wide variety of striking pharmacological actions, but also to be present in many if not all mammalian tissues. They have an unusual chemical structure, being 20-carbon fatty acids derived enzymically from the essential fatty acids by cyclization and oxidation. Converting enzymes have been demonstrated in many tissues; they are especially active in the vesicular glands of the sheep, which are used for a practical method of biosynthesis. Physiological roles for these recently rediscovered compounds are yet to be established, but whenever substances are found in tissues which in very small doses can affect the function of these tissues, there is the possibility that they are regulators of physiological activity. Each effect of one or another prostaglandin suggests a corresponding physiological role, whether stimulatory or inhibitory, on such systems as smooth muscle, nerves, the circulation, and the reproductive organs. In the last named, roles in relation to fertility and coitus and later possible action in relation to labor and postpartum uterine contraction have been proposed. Prostaglandins liberated by nerve stimulation, which then have actions opposite to that of the nerve stimulation, suggests a role as feed-back inhibitors. Thus, sympathetic nerve stimulation to adipose tissue induces both lipolysis and the release of antilipolytic prostaglandins, and vagal stimulation to the stomach, both secretion and the release of prostaglandins with powerful antisecretory actions. On the other hand, the ability of minute amounts of certain prostaglandins, inactive in their own right, to potentiate other agonists, suggests a more general role on ion transport or membrane function. Now days, many prostaglandin analogues are in market, while several hundred are in clinical trials.

Reference Id: PHARMATUTOR-ART-1967

INTRODUCTION:
The eicosanoids (specifically the prostaglandins) were discovered in 1935 when a Swedish physiologist and Nobel laureate, Ulf von Euler, and other investigators found That extracts of seminal vesicles or of human semen lowered blood pressure and caused Contraction of strips of uterine tissue. Von Euler coined the term prostaglandin because he assumed that the active material came exclusively from the prostate gland. Eicosanoids are 20-carbon fatty acids that are produced in a variety of tissues and that mediate an array of physiologic and pathologic processes. They consist of the prostaglandins PGA through PGH, which are present in nearly all mammalian tissues where they regulate function; the related thromboxanes, which are found in blood platelets; and the leukotrienes, whose biological effects include respiratory, vascular, and intestinal activities. All of the eicosanoids are derived from the oxidative metabolism of arachidonic acid (5, 8, 11, 14-eicosatetraenoic acid) through what is referred to as the “arachidonic acid cascade. They generally act locally, either affecting cell that makes them or nearby cells; in most cases, eicosanoids are not systemic hormones, because of their short half-lives.

Prostaglandins (PGs) consist of an oxygenated cyclopentane/pentene ring with a heptenoic or heptanoic acid side and a octanol side chain on adjacent carbon atoms of the ring. This nasic structural unit is referred to as a prostanoic or prostenoic acid. Each PG differs from the others in the substitution pattern in the cyclopentane ring and the side chains and these differences are responsible for the different biologic activities of the members of the prostaglandin group. Prostaglandins are broadly classified as PGA, PGB, PGC, PGD, PGE, PGF, PGG, and PGH based on their cyclopentane/pentene ring substitution patterns. Each general PG class is sub classified based on the degree of unsaturation (i.e. PGE1, PGE2, PGF2). The letters and numbers that follow the initial PG abbreviation indicate the nature of the unsaturation and substitution. For example, the subscript 1 in PGE1 indicates one double bond in the side chains, while the subscript 2 inPGE2 indicates two double bonds in the side chains (see Biosynthesis Section and Drug monographs that follow. The thromboxanes (also prostanoids) and leukotrienes are also sub-classified based on substitution patterns and degree of substitution as shown below.

ECOSANOID BIOSYNTHESYS:
The key precursor in eicosanoid biosynthetic pathways is arachidonic acid that is formed from linolenic acid through reactions catalyzed by a series of enzymes that dehydrate fatty  acids. Cells store arachidonic acid as a component of membrane phospholipids such as phosphoinositol. In response to an appropriate stimulus, arachidonic acid is liberated from the storage lipid by an enzymatic reaction catalyzed by phospholipase A2. There area number of drugs, such as the glucocorticoids, that modulate PLA2 and thereby influence (inhibit) eicosanoid production. The conversion of free arachidonic acid to prostaglandins and other eicosanoids is initiated oxidative enzymes of the cyclooxygenase (PGHsynthase)and lipoxygenase families.The key precursor in eicosanoid biosynthetic pathways is arachidonic acid that is formed from linolenic acid through reactions catalyzed by a series of enzymes that dehydrate fatty acids. Cells store arachidonic acid as a component of membrane phospholipids such as phosphoinositol. In response to an appropriate stimulus, arachidonic acid is liberated from the storage lipid by an enzymatic reaction catalyzed by phospholipase A2. There are a number of drugs, such as the glucocorticoids, that modulate PLA2 and thereby influence (inhibit) eicosanoid production. The conversion of free arachidonic acid to prostaglandins and other eicosanoids is initiated oxidative enzymes of the cyclooxygenase (PGHsynthase) and lipoxygenase families. Cyclooxygenase stereospecifically adds two molecules of oxygen to arachidonic acid to form the unique bicyclic endoperoxide PGG2. The hydroperoxide group of PGG2 is then reduced by the cyclooxygenase (PGH-synthase) to yield the single 15(S)-alcohol PGH2. Two different isozymes of cyclooxygenase exist, a constitutive form (COX-1) and a highly inducible form (COX-2). The COX isozymes are variably inhibited by ω3-fatty acids (eicosapentaenoic acid and dcosahexaenoic acid) as well as the traditional NSAID drugs and the COX-2 inhibitors. The structure and inhibition of COX isozymes are discussed in more detail in the NSAID Chapter. PGH2 serves as a “branch point” for specific enzymes leading to the formation of prostacyclin (PGI2), the various prostaglandins as well as the thromboxanes. Which derivatives form from PGH2 is determined by specific tissues and their metabolic capabilities and physiologic functions as discussed in the next section. The lipoxygenase pathway of arachidonic acid metabolism produces a variety of acyclic lipid peroxides (hydroperoxyeicosatetraenoic acids or HPETEs) which can be reduced to the corresponding alcohols (hydroxyeicosatetraenoic acids or HETEs). The HPETEs can yield the oxirane (epoxide) LTA4 which may be hydrolyzed to LTB4 or conjugated with glutathione to yield LTC4. Modification of the glutathione conjugate amino acids by hydrolysis yields the other leukotrienes LTD4, LTE4 and LTF4. The roles of various leukotrienes are summarized in the section that follows.

Biosynthesis of prostaglandins (FIG-1)

Biosynthesis of leukotrienes (FIG-2)

Pharmacological actions of Ecosanoids:
The prostaglandins are important mediators of normal physiologic events and have been Implicated in a variety of pathologies. They have been implicated in inflammation, pain, Pyrexia, cardiovascular disease, renal disease, cancer, glaucoma, allergic rhinitis, asthma Preterm labor, male sexual dysfunction and osteoporosis. This has led to the development of a number of prostaglandin drug products as indicated in the Table-1 below and discussed in more detail.

Prostaglandin Drug Products Used Worldwide (Table-1)

Prostaglandin effects are usually manifested locally around the site of prostaglandin synthesis (paracrine) and their actions are multiple and variable (stimulatory or inhibitory) depending on tissue type and the nature of the receptors with which they interact. To date eight prostanoid receptors have been cloned and characterized. Note that these receptors are coupled to either phospholipase C (PLC) or adenylate cyclase (AC) and, in the case of adenylate cyclase, the action of the PGs may be stimulatory or inhibitory. The physiologic actions of various eicosanoids are summarized in the Table at the end ofthis section. Prostaglandins are powerful vasodilators; that is, they relax the muscles in the walls of blood vessels so that the diameters become larger and there is less resistance to the flow. Consequently, the blood pressure falls. Again, the effect can be local. An important example of the vasodilatation effect of prostaglandins is in the kidney, where widespread vasodilatation leads to an increase in the flow of blood to the kidney and increased excretion of salt in the urine. Thromboxanes, on the other hand, are powerful vasoconstrictors in the same setting.

Receptors for prostaglandins (Table-2)
There are currently ten known prostaglandin receptors on various cell types. Prostaglandins bind to a subfamily of cell surface seven-transmembrane receptors, G-protein-coupled receptors. These receptors are named as

Summary of physiological actions of prostaglandins (Table-3)

They are mediators and have a variety of strong physiological effects, such as regulating the contraction and relaxation of smooth muscle tissue. Prostaglandins are not endocrine hormones, but autocrine or paracrine, which are locally acting messenger molecules. They differ from hormones in that they are not produced at a discrete site but in many places throughout the human body. Also, their target cells are present in the immediate vicinity of the site of their secretion

Table-4: Few marketed prostaglandin analogues with various biological activities

CONCLUSION:
Prostanoids^[21] can promote or restrain acute inflammation. Products of COX-2 in particular may also contribute to resolution of inflammation in certain settings. Presently, we have little information on which products of COX-2 might subserve this role or indeed if the dominant factors reflect rediversion of the arachidonic acid substrate to other metabolic pathways consequent to deletion or inhibition of COX-2. As with cyclopentanone prostanoids, many arachidonate derivatives, including transcellular products, when synthesized and administered as exogenous compounds, can promote resolution in models of inflammation. However, rigorous physico-chemical evidence for the formation of the endogenous species in relevant quantities to subserve this role in vivo is limited. Elucidation of whether and how prostanoids might restrain inflammation and how substrate modification, such as with fish oils, might exploit this understanding is currently a focus of much research from which novel therapeutic strategies are likely to emerge.

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