Selective estrogen receptor-beta (SERM-beta) compounds modulate raphe nuclei tryptophan hydroxylase-1 (TPH-1) mRNA expression and cause antidepressant-like effects in the forced swim test.
Estrogen acts through two molecularly distinct receptors termed estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) which bind estradiol with similar affinities and mediate the effects of estrogen throughout the body. ERα plays a major role in reproductive physiology and behavior, and mediates classic estrogen signaling in such tissues as the uterus, mammary gland, and skeleton. ERβ, however, modulates estrogen signaling in the ovary, the immune system, prostate, gastrointestinal tract, and hypothalamus, and there is some evidence that ERβ can regulate ERα activity. Moreover, ERβ knockout studies and receptor distribution analyses in the CNS suggest that this receptor may play a role in the modulation of mood and cognition. In recent years several ERβ-specific compounds (selective estrogen receptor beta modulators; SERM-beta) have become available, and research suggests potential utility of these compounds in menopausal symptom relief, breast cancer prevention, diseases that have an inflammatory component, osteoporosis, cardiovascular disease, and inflammatory bowel disease, as well as modulation of mood, and anxiety. Here we demonstrate an antidepressant-like effect obtained using two SERM-beta compounds, SERM-beta1 and SERM-beta2. These compounds exhibit full agonist activity at ERβ in a cell based estrogen response element (ERE) transactivation assay. SERM-beta1 and 2 are non-proliferative with respect to breast as determined using the MCF-7 breast cancer cell-based assay and non-proliferative in the uterus as determined by assessing the effects of SERM-beta compounds on immature rat uterine weight and murine uterine weight. In vivo SERM-beta1 and 2 are brain penetrant and display dose dependent efficacy in the murine dorsal raphe assays for induction of tryptophan hydroxylase mRNA and progesterone receptor protein. These compounds show activity in the murine forced swim test and promote hippocampal neurogenesis acutely in rats. Taken together these data suggest that ERβ may play an important role in modulating mood and the ERβ specific compounds described herein will be useful tools for probing the utility of an ERβ agonist for treating neuroendocrine-related mood disturbance and menopausal symptoms.
Merck Research Laboratories, Rahway, NJ, USA. jclark@drexelmed.edu
J A
JA
Clark
S
S
Alves
C
C
Gundlah
B
B
Rocha
E T
ET
Birzin
S-J
SJ
Cai
R
R
Flick
E
E
Hayes
K
K
Ho
S
S
Warrier
L
L
Pai
J
J
Yudkovitz
R
R
Fleischer
L
L
Colwell
S
S
Li
H
H
Wilkinson
J
J
Schaeffer
R
R
Wilkening
E
E
Mattingly
M
M
Hammond
S P
SP
Rohrer
D000818:Animals; D000928:Antidepressive Agents; D001812:Blood-Brain Barrier / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000187:drug effects; D047629:Estrogen Receptor beta / Q000187:drug effects*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D055495:Neurogenesis / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D010957:Plasmids / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D011903:Raphe Nuclei / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013550:Swimming / Q000523:psychology*; D015533:Transcriptional Activation / Q000187:drug effects; D014365:Tryptophan Hydroxylase / Q000096:biosynthesis* / Q000235:genetics; D014599:Uterus / Q000033:anatomy & histology / Q000502:physiology
D000928:Antidepressive Agents; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D012333:RNA, Messenger; D011944:Receptors, Androgen; D011980:Receptors, Progesterone; D020845:Selective Estrogen Receptor Modulators; D004247:DNA; D014365:Tryptophan Hydroxylase; C504570:tph1 protein, rat