Effects of CP-336,156, a new, nonsteroidal estrogen agonist/antagonist, on bone, serum cholesterol, uterus and body composition in rat models

Endocrinology. 1998 Apr;139(4):2068-76. doi: 10.1210/endo.139.4.5902.

Abstract

We have discovered a new, nonsteroidal, potent estrogen agonist/antagonist, CP-336,156. CP-336,156 binds selectively and with high affinity to the human estrogen receptor-alpha with a half-inhibition concentration of 1.5 nM, which is similar to that seen with estradiol (4.8 nM). When given orally to immature (3-week-old) female Sprague-Dawley rats for 3 days at doses of 0.1, 1.0, 10, or 100 microg/kg x day, unlike 17alpha-ethynyl estradiol, CP-336,156 had no effect on uterine wet or dry weight. Similarly, no uterine hypertrophy was observed in aged (17-month-old) female rats treated (p.o.) with CP-336,156 at 10 or 100 microg/kg x day for 28 days. We also found that CP-336,156 decreased total serum cholesterol and fat body mass and had no effect on lean body mass in these aged female rats. In 5-month-old ovariectomized (OVX) Sprague-Dawley female rats, CP-336,156 completely prevented OVX-induced increases in body weight gain, total serum cholesterol, and serum osteocalcin at doses between 10 and 1000 microg/kg x day after 4 weeks. At these doses, CP-336,156 completely prevented OVX-induced bone loss and inhibited the increased bone turnover associated with estrogen deficiency in lumbar vertebrae, proximal tibiae, and distal femora. Similar to estrogen, CP-336,156 induced apoptosis and p53 expression with a concomitant decrease in the number of tartrate-resistant acid phosphatase-positive multinuclear cells in rat bone marrow cell cultures in vitro, suggesting that the induction of apoptosis may be a mechanism for the estrogenic activities of CP-336,156 in bone. In summary, CP-336,156 is a new, orally active, nonsteroidal, potent estrogen agonist/antagonist that has similar effects in bone as estradiol but without the uterine-stimulating effects associated with estradiol in rats.

MeSH terms

  • Adipose Tissue
  • Aging
  • Animals
  • Apoptosis
  • Body Composition / drug effects*
  • Bone Marrow Cells / drug effects
  • Bone and Bones / drug effects*
  • Cells, Cultured
  • Cholesterol / blood*
  • Estrogen Antagonists / pharmacology*
  • Female
  • Gene Expression / drug effects
  • Genes, p53
  • Organ Size / drug effects
  • Osteocalcin / blood
  • Ovariectomy
  • Pyrrolidines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Estrogen / metabolism
  • Tetrahydronaphthalenes / pharmacology*
  • Uterus / anatomy & histology
  • Uterus / drug effects*
  • Weight Gain / drug effects

Substances

  • Estrogen Antagonists
  • Pyrrolidines
  • Receptors, Estrogen
  • Tetrahydronaphthalenes
  • Osteocalcin
  • Lasofoxifene
  • Cholesterol