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Prostaglandin analogs of the PGF2 alpha, 15-epi-PGF2 alpha, and PGE2 type bearing the following methyl substitution patterns -- 15-Me, 16, 16-(Me)2, 17, 17-(Me)2, and 18, 18, 20-(Me)3 -- and analogs constrained to "hairpin" alignment [via 1, (omega-1)-olide formation] and to "non-hairpin" arrangements [via 1, 9- and 1, 15-olide formation] are compared in the following biological assays: contraction of uterine and gastro-intestinal smooth muscle strips, luteolytic antifertility potency in the hamster, binding affinity to two different PGF2 alpha-receptor preparations from bovine corpora lutea, binding to the PGE-specific receptors from rat kidney and liver, inhibition of ADP- induced aggregation of human platelet-rich-plasma, and the effect on rat blood blood pressure. The methylated prostaglandins were also concerted to the corresponding prostacyclins and examined as to action on the platelet and on rat blood pressure. All evidence points to topographically distinct receptors for F2 alpha-, E- and I2- type prostaglandins. Cross-reactivity is reduced in most of the analogs examined. Independent of the target organ or tissue, the receptors show common features based on the functional class of PG recognized. "Hairpin" alignment improves binding (and potency) only for the PGF2 alpha specific assays. PGE-specific binding and potency is disrupted to an increasing extent as the chain branching point is moved further from the 15-hydroxyl center. In contrast 16, 16-dimethylation is particularly disruptive for the PGI2/E1 platelet receptor interaction.

Our previously published prostaglandin (PG) synthesis route, in which the omega-chain is added in the penultimate step, provides facile access to a wide variety of omega-chain variant PG analogs. Each series requires only the synthesis of the appropriate methylated acylphosphonate for the Emmons' condensation. The syntheses of analogs bearing the following methylation patterns are detailed: 15-Me; 17,17-(Me) 2; 17, 17, 20-(Me) 3; 18, 18, 20-(Me) 3; 15, 18, 18, 20-(Me) 4; and 15-OMe-18, 18, 20- (Me) 3. The well-known 16., 16-dimethyl prostaglandins have also been prepared by this sequence. The synthesis of 16, 16-tetramethylene-PG analogs is also described.

Prostaglandin analogs of the E- and F2α-functional type, which are constrined to conformations in which the side-chains are close in space and specifically aligned in the terminal portions by covalent bonding, have been synthesized. These analogs are 1, (ω-1)-macrolides. The syntheses proceed from aldehyde intermediate I via the Emmon's condensation with dimethyl n-(dimethyl-t-butyl-silyloxy) 2-oxoalkylphosphonate anions (IIa or b). The macrolide closures were performed using 2,2′-dipyridyl disulfide. For the synthesis of 9-ketoprostaglandin macrolides, a free 9-hydroxy is available for oxidation after macrolide closure, so long as the 9-position is protected as the acetate rather than benzoate. Chiroptical data revealed that the conformations of the macrolide prostaglandins are unchanged (relative to the natural uncosntrained prostaglandins) in the vicinity of the five-membered ring and the allyl alcohol unit by the formation of the macrolide linkage.