dinoprost and Osteoporosis

A series of novel C(1) alkylphosphinic acid analogues of the prostaglandin-F family have been evaluated at the eight human prostaglandin receptors for potential use in the treatment of osteoporosis. Using molecular modeling as a tool for structure-based drug design, we have discovered that the phosphinic acid moiety (P(O)(OH)R) behaves as an isostere for the C(1) carboxylic acid in the human prostaglandin FP binding assay in vitro and possesses enhanced hFP receptor selectivity when compared to the parent carboxylic acid. When evaluated in vivo, the methyl phosphinic acid analogue (4b) produced a bone anabolic response in rats, returning bone mineral volume (BMV) [corrected], to intact levels in the distal femur in the ovariectomized rat (OVX) model. These results suggest that prostaglandins of this class may be useful agents in the treatment of diseases associated with bone loss.

Topics: Absorptiometry, Photon; Amino Acid Sequence; Animals; Binding, Competitive; Bone and Bones; Bone Density; COS Cells; Dinoprost; Female; Humans; Models, Molecular; Molecular Sequence Data; Osteoporosis; Ovariectomy; Phosphinic Acids; Prostaglandins F, Synthetic; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin; Structure-Activity Relationship; Tomography, X-Ray Computed; Transfection

Free radicals have been shown to be involved in bone resorption in vitro and in rodents. We studied the effect of oxidative stress on bone mineral density (BMD) in 48 women and 53 men from a population-based study. The levels of 8-iso-PGF(2alpha) (a major F(2)-isoprostane and a biomarker of oxidative stress) and a control, 15-keto-dihydro-PGF(2alpha) (a biomarker of inflammatory response), were measured in urinary samples and their association with BMD and quantitative ultrasound (QUS) measurements were examined. In multivariate linear regression analyses, 8-iso-PGF(2alpha) levels were negatively associated with both BMD and QUS. In contrast, no association was found for 15-keto-dihydro-PGF(2alpha). Our findings establish a biochemical link between increased oxidative stress and reduced bone density and provide a rational for further studies investigating the role of pro- and antioxidants in osteoporosis.

Topics: Adult; Aged; Biomarkers; Bone Density; Dinoprost; F2-Isoprostanes; Female; Humans; Male; Middle Aged; Osteoporosis; Oxidative Stress

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.

Topics: Animals; Binding, Competitive; COS Cells; Drug Design; Humans; Ligands; Models, Molecular; Osteoporosis; Prostaglandins F; Radioligand Assay; Rats; Receptors, Prostaglandin; Stereoisomerism; Structure-Activity Relationship

A novel class of saturated prostaglandin F2alpha sulfonamide analogs have been synthesized and evaluated in the human FP receptor binding assay for potential use in the treatment of osteoporosis. These compounds have been modified at the C1 carboxylic acid moiety and at the C16-C20 region of the prostaglandin. Based on the structure-activity relationships, it was found that at C1, the aryl sulfonamide analogs possessed greater affinity for the hFP receptor when compared to alkyl sulfonamides. When the sulfonamide was introduced into the C16-C20 region (omega chain) of the prostaglandin, a significant reduction in binding was observed. These results are discussed within the framework of a proposed model for the human FP receptor.

Topics: Dinoprost; Magnetic Resonance Spectroscopy; Osteoporosis; Receptors, Prostaglandin; Structure-Activity Relationship; Sulfonamides

A new hypothesis is presented for the first time to explain the etiology of osteoporosis. Prostaglandins (E2 and F2 alpha) at precise concentrations, have been observed to be involved in bone formation. A close association exists between levels of prostaglandins (E2 and F2 alpha) demonstrated in the neonatal mouse leading to bone formation, with estimated prostaglandins (E2 and F2 alpha) concentrations reported in man. Several hormones (vasopressin, oxytocin, luteinizing hormone, follicle-stimulating hormone, cortisol, estradiol, and testosterone) can indirectly affect prostaglandin formation leading to reduced bone formation. The association between these hormones and prostaglandins (E2 and F2 alpha) explains the physiological mechanism whereby estradiol can be effective for the treatment of osteoporosis. This association also explains the etiology of lumbar spondylitis/spondylodynia, reasons for complaints of increased pain in wet cold weather among arthritics and a multitude of other events. Mechanisms related to this interaction between various hormones and the effect of prostaglandins (E2 and F2 alpha) on bone formation are discussed.

Topics: Animals; Bone and Bones; Bone Development; Bone Resorption; Calcitonin; Cholecalciferol; Cortisone; Dinoprost; Dinoprostone; Female; Humans; Menopause; Models, Biological; Osteoporosis; Oxytocin; Parathyroid Hormone; Vasopressins