Design and Synthesis of 13,14-Dihydro Prostaglandin F_1α Analogues as Potent and Selective Ligands for the Human FP Receptor

Abstract

The in vitro evaluation of a new class of potential bone anabolic agents for the treatment of osteoporosis is described. These compounds are potent and selective ligands for the human prostaglandin F receptor (hFP receptor). The compounds lack the olefin unsaturation required for potency in the natural ligand PGF(2)(alpha) yet retain binding affinity for the hFP receptor in the nanomolar to micromolar range. Removal of the alkenes also results in a better selectivity ratio for the hFP receptor over the other prostaglandin receptors tested. A rationale for the selectivity differences of various analogues, based on ligand docking experiments to a putative hFP receptor model, is also described.

Characterization of Binding Affinity of CJ-023,423 for Human Prostanoid EP₄ Receptor

“…Next, to explore the possible mechanism of this effect, we examined the binding affinities of 2 structurally close analogs of CJ-023,423, CJ-022,455 and CJ-019,957. The pH conditions of the assay buffer minimally influenced the binding affinity of CJ-022,455 for human EP 4 receptor. The conformational (3-dimensional structural) properties of CJ-022,455 are very similar to those of CJ-023,423.…”

“…Unfortunately, a 3-dimensional model for EP 4 -receptor-ligand interaction has yet to be identified. It has therefore been difficult to apply information from a fitting model between the EP 4 receptor and relevant compounds to structure-activity relationship studies to discover compounds with high affinities for EP 4 receptors.…”

“…Unfortunately, a 3-dimensional model for EP 4 -receptor-ligand interaction has yet to be identified. It has therefore been difficult to apply information from a fitting model between the EP 4 receptor and relevant compounds to structure-activity relationship studies to discover compounds with high affinities for EP 4 receptors. Thus, we previously used a radioligand receptor binding assay as the primary screen in our discovery program for a PGE 2 EP 4 receptor antagonist, and we discovered a potent and selective EP 4 antagonist, CJ-023,423 ( fig.…”

“…DMEM: Dulbecco᾽s modified eagle medium containing 0.1% NaN 3 , pH 7.4. 4 receptor under isotonic buffer condition were influenced by pH (1.4 vs. 7.9 nmol/l; table 1 ).…”

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using a computational ligand-docking approach, which is useful in understanding the interactions between the lead compound and receptors in the development of the structure-activity relationship [4] . Unfortunately, a 3-dimensional model for EP 4 -receptor-ligand interaction has yet to be identified.

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