ABSTRACT
INTRODUCTION: There is evidence that supports a role for Vitamin D (Vit. D) in muscle. The exact mechanism by which Vit. D deficiency impairs muscle strength and function is not clear. METHODS: Three-week-old mice were fed diets with varied combinations of Vit. D and Ca2+ deficiency. Behavioral testing, genomic and protein analysis, and muscle histology were performed with a focus on neuromuscular junction (NMJ) -related genes. RESULTS: Vit. D and Ca2+ deficient mice performed more poorly on given behavioral tasks than animals with Vit. D deficiency alone. Genomic and protein analysis of the soleus and tibialis anterior muscles revealed changes in several Vit. D metabolic, NMJ-related, and protein chaperoning and refolding genes. CONCLUSIONS: These data suggest that detrimental effects of a Vit. D deficient or a Vit. D and Ca2+ deficient diet may be a result of differential alterations in the structure and function of the NMJ and a lack of a sustained stress response in muscles. Muscle Nerve 54: 1120-1132, 2016.
Subject(s)
Ascorbic Acid Deficiency/pathology , Diet/adverse effects , Gene Expression Regulation/physiology , Hindlimb/pathology , Muscle Fibers, Skeletal/physiology , Neuromuscular Junction/physiopathology , Age Factors , Animals , Ascorbic Acid Deficiency/blood , Ascorbic Acid Deficiency/etiology , Ascorbic Acid Deficiency/metabolism , Calcium/metabolism , Disease Models, Animal , Heat-Shock Proteins/genetics , Heat-Shock Proteins/metabolism , Locomotion , Male , Mice , Mice, Inbred C57BL , Muscle Strength , Parathyroid Hormone/blood , Phosphorus/blood , Postural Balance , Psychomotor Performance , Vitamin D/metabolismABSTRACT
We report the synthesis and characterization of novel 3-aryl indoles as potent and efficacious progesterone receptor (PR) antagonists with potential for the treatment of uterine fibroids. These compounds demonstrated excellent selectivity over other steroid nuclear hormone receptors such as the mineralocorticoid receptor (MR). They were prepared from 2-bromo-6-nitro indole in four to six steps using a Suzuki cross-coupling as the key step. Compound 8f was orally active in the complement 3 model of progesterone antagonism in the rat uterus and demonstrated partial antagonism in the McPhail model of progesterone activity.
ABSTRACT
A selective estrogen receptor modulator (SERM) for the potential treatment of hot flushes is described. (R)-(+)-7,9-difluoro-5-[4-(2-piperidin-1-ylethoxy)phenyl]-5H-6-oxachrysen-2-ol, LSN2120310, potently binds ERalpha and ERbeta and is an antagonist in MCF-7 breast adenocarcinoma and Ishikawa uterine cancer cell lines. The compound is a potent estrogen antagonist in the rat uterus. In ovariectomized rats, the compound lowers cholesterol, maintains bone mineral density, and is efficacious in a morphine dependent rat model of hot flush efficacy.
Subject(s)
Benzopyrans/chemical synthesis , Estrogen Antagonists/chemical synthesis , Hot Flashes/drug therapy , Naphthalenes/chemical synthesis , Selective Estrogen Receptor Modulators/chemical synthesis , Adenocarcinoma , Animals , Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Benzopyrans/chemistry , Benzopyrans/pharmacology , Bone Density/drug effects , Breast Neoplasms , Cell Line, Tumor , Cell Proliferation/drug effects , Cholesterol/blood , Estrogen Antagonists/chemistry , Estrogen Antagonists/pharmacology , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism , Female , Humans , Morphine/pharmacology , Naphthalenes/chemistry , Naphthalenes/pharmacology , Ovariectomy , Rats , Rats, Sprague-Dawley , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/pharmacology , Stereoisomerism , Uterine Neoplasms , Uterus/drug effects , Uterus/growth & developmentABSTRACT
For selective estrogen receptor modulators (SERMs), the orientation of the basic side chain relative to the SERM core has a significant impact on function. The synthesis and biological evaluation of two series of SERMs are disclosed, where the ligand side chain is constrained to adopt a defined orientation. Compounds where the side chain is forced into the plane of the SERM core have a different profile compared to those compounds where the side chain is pseudo-orthogonal, particularly with regard to antagonism of estradiol action on an Ishikawa uterine cell line.
