Modified prostaglandins: New possibilities for the pharmacological control of immunodeficient states

Abstract

The role of exogenous prostaglandins (PGs) as immune response and allergic inflammation regulators and the existing notions of the interaction between synthetic PGs or their modified analogs with prostanoid receptors are considered. Based on the principles of structural complementarity, the immunotropic effects of new synthetic 11-deoxyprostanoids of the E1, E2, and F2α series, modified at the α-and ω-chains and containing pharmacophores at various positions of the prostanoid skeleton, were studied as dependent on the dose and the chemical structure. It is established that prostanoids of the E series, which are deprived of oxo and hydroxy groups at the cyclopentane ring but contain a complete or nearly complete α-chain and a malonic ether fragment at the ω-chain, exhibit no immunotropic activity. On the other hand, the PG analogs containing 9-keto groups enhance both the cellular and humoral immunogenesis in mice immunized (sensitized) with sheep red blood cells. The presence of an oxo group at position 7 is also important for the immunopositive response and the pharmacological activity. The enhancement of the ligand — receptor interaction is retained upon replacing the cyclopentane fragment by the bicycloheptane moiety. The ω-chain modification by incorporating a sulfur heteroatom at position 13 caused no substantial changes in the immunomodulating activity, whereas the ω-chain modification resulting in the formation of 1-amino-3-oxo-oct-1-enyl fragment can be considered as an important condition for obtaining immunopositive prostanoids. As a rule, the ability to enhance the humoral immunity was increased on going from the E to F series of prostanoids. The pharmacodynamic parameters of the immune response evidenced a high affinity of F-prostanoids to EP receptors. It can be suggested that F-prostanoids may act as agonists of these receptors. From this standpoint, a decrease in the immunoactivity of compounds having too bulky fragments in the ω-chain is quite reasonable. Thus, some of the ligands affine to prostanoid receptors are worthy of attention as prototypes of safe and efficient low-molecular immunoregulators of a new generation.