Prostaglandins & Thromboxane

Prostaglandins were the first commercial products offered by Cayman Chemical more than fifteen years ago. Our many years of devotion to this product area have resulted in a very comprehensive group of autacoids that can be confusing at first, especially for those new to this field.

Prostaglandins (PGs) contain prostanoic acid as the central structural element. The carbon numbering system for this molecule is illustrated below. The nomenclature of PGs is derived from two structural features in the prostanoic acid framework. First, the letter component (PGA, PGB) identifies the functional groups on the cyclopentane ring. Second, the numerical subscript (PGA1, PGA2) indicates the number of double bonds in the side chains, reflecting the degree of unsaturation of the precursor fatty acid. For instance, PGD1, PGD2, and PGD3 are the putative products of cyclooxygenase metabolism of dihomo-linolenic, arachidonic, and eicosa-pentaenoic acids, respectively.

Prostanoic Acid

The presense of the prostaglandins is pervasive throughout all biological systems. Since the activity of each prostaglandin is specific to individual cell types within different tissues, it is difficult to make general statements about the biological role of a given prostanoid. Referring to prostaglandins in physiologic terms such as 'hypotensive' or 'inflammatory' neglects many of the other intricate cellular interactions that may also be occurring. It is more accurate to discuss prostaglandin activity in relation to cell and receptor type. Cells are characterized by a unique quantitative and temporal distribution of prostaglandin receptor subtype expression; further, each receptor type has been linked to specific transduction effector mechanisms such as the inositol triphosphate/diacyl glycerol or cyclic nucleotide pathways. Although still incomplete, substantial progress has recently been made in the characterization of prostaglandin receptors, many of which have now been cloned. The table of prostaglandin receptor nomenclature is a guide to further reading in the literature. Once a prostaglandin has been identified as having a predictable and desired activity on a given cell type, the search for more potent, stable analogs begins. Over the years we have introduced compounds with numerous structural modifications, producing analogs with predictable changes in biologic activity. Some of these are:

16,16-dimethyl: Confers resistance to metabolism by Prostaglandin 15-dehydrogenase; generally results in prolonged duration of action and increased potency;
15(S)-15-methyl: Renders analogs inert to C-15 metabolism; often results in 100-fold increase in potency;
-for-O substitution (U-46619, Carba-prostacyclin): Converts chemically fragile species with half-lives less than five minutes into rugged analogs stable for weeks from pH 2-10; usually is accompanied by a reduction (up to 50%) in molar biological potency.

Prostanoid Ring Variants

Prostanoid Ring Variants In spite of their structural diversity, prostaglandins as a class are relatively easy to handle. Those prostaglandins that are naturally crystalline are very stable in this form and are sold as crystalline powders. They can remain unchanged after a decade at -20°C. Other prostaglandins are thick, viscous oils in the pure state and have lower stability due to the presence of dissolved oxygen and minute amounts of water. In order to aid in the storage and handling of these oils, most are formulated as solutions in the inert, volatile solvent, methyl acetate. This stabilizing vehicle can easily be evaporated with a gentle stream of dry argon or nitrogen just prior to use. Prostaglandins are generally lipophilic in character and somewhat resistant to forming aqueous solutions. Clear instructions on the insert accompanying each vial give some suggestions about using ethanol and/or bicarbonate to help solubilize the prostaglandin. In some cases such as PGF2?, we have prepared the tromethamine salt as a complimentary formulation to the free acid. Tromethamine salts dissolve much more readily in water, and should be considered if the preparation of relatively concentrated aqueous solutions are intended.

Suggestions for further reading

Nelson, N.A. Prostaglandin nomenclature. J. Med. Chem. 17, 911-918 (1974).
Nelson, N.A., Kelly, R.C., and Johnson, R.A. Prostaglandins and the arachidonic acid cascade. C&EN 30-44 (1982).
Frolich, J.C. Measurement of icosanoids. Prostaglandins 27, 349-369 (1984).
Oates, J.A., Fitzgerald, G.A., Branch, R.A., et al. Clinical implications of prostaglandin and thromboxane A2 formation. The New England Journal of Medicine 319, 689-767 (1988).

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