Selective progesterone receptor modulator
Encyclopedia
A selective progesterone receptor modulator (SPRM) is an agent that acts on the progesterone
receptor
. A characteristic that distinguishes such substances from receptor full agonists (such as progesterone
) and full antagonists (such as mifepristone
) is that their action differs in different tissues (agonist in some while antagonist in others). This mixed agonist/agonist profile of action leads to selective stimulation or inhibition progesterone-like action in different tissues and furthermore raises the possibility of dissociation of desirable therapeutic effects from undesirable side effects in synthetic progesterone receptor drug candidates.
While these SPRMs have been effective for the treatment of uterine fibroids, development of side effects such as endometrial thickening has limited their administration to no longer than three to four months.
, but nevertheless bind to the same progesterone receptor
. In humans, there is only one gene that codes for the receptor, but two splice variants (PR-A and -B) arising from this single gene each with a somewhat different tissue distribution and intrinsic functional activity in response to ligand binding (agonist vs. antagonist). In addition, synthetic SPRMs may have some binding selectivity between the two isoforms, although this is unlikely as the ligand binding domains of the two isoforms are identical.
A more likely origin of the tissue selectivity of SPRMs is what conformational preference these ligands induce in the receptor. The ligand binding domain of the receptor is in equilibrium between two different conformations. The first is an agonist conformation which favors the binding of coactivator
proteins which in turn favors upregulation of gene transcription. The second is an antagonistic conformation which in contrast favors the binding of corepressor
s and as a consequence down regulation of gene expression. Full agonists such as progesterone which display agonist properties in all tissues, strongly shift the conformational equilibrium in the agonist direction. Conversely full antagonists such as RU-486 strongly shift the equilibrium in the antagonist direction. Finally, the overall ratio of concentrations of coactivator to corepressor may differ in different cell types.
When SPRMs bind to the progesterone receptor, the equilibrium between the two conformational states is more closely balanced and hence more easily perturbed by differences in the cellular environment. In tissues where the concentration of coactivators is higher than corepressors, the excess coactivators drive the equilibrium in the agonist direction. Conversely in tissues where corepressor concentration is higher the equilibrium is driven in the antagonist direction. Hence SPRMs display agonist activity in tissues where coactivators predominate and antagonist activity where corepressors are in excess.
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
receptor
Progesterone receptor
The progesterone receptor also known as NR3C3 , is an intracellular steroid receptor that specifically binds progesterone...
. A characteristic that distinguishes such substances from receptor full agonists (such as progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
) and full antagonists (such as mifepristone
Mifepristone
Mifepristone is a synthetic steroid compound used as a pharmaceutical. It is a progesterone receptor antagonist used as an abortifacient in the first months of pregnancy, and in smaller doses as an emergency contraceptive. During early trials, it was known as RU-38486 or simply RU-486, its...
) is that their action differs in different tissues (agonist in some while antagonist in others). This mixed agonist/agonist profile of action leads to selective stimulation or inhibition progesterone-like action in different tissues and furthermore raises the possibility of dissociation of desirable therapeutic effects from undesirable side effects in synthetic progesterone receptor drug candidates.
Members
Members include:- Ulipristal acetateUlipristal acetateUlipristal acetate is a selective progesterone receptor modulator for emergency contraception within 120 hours after an unprotected intercourse or contraceptive failure...
("Ella") - AsoprisnilAsoprisnilAsoprisnil is an investigational selective progesterone receptor modulator developed by Schering and TAP Pharmaceutical Products, tested for treatment of progesterone sensitive myomata....
(J867; status uncertain) - CDB-4124CDB-4124CDB-4124 is an investigational selective progesterone receptor modulator, tested for treatment of progesterone sensitive myomata., it is undergoing Phase II and III clinical trials....
(Proellex, Progenta; under development)
Uses
SPRMs are under development for the following uses:- Asoprisnil and CDB-4124 are both under investigation (2005) for the medical treatment of uterine leiomyomaLeiomyomaA leiomyoma is a benign smooth muscle neoplasm that is not premalignant. They can occur in any organ, but the most common forms occur in the uterus, small bowel and the esophagus.- Etymology:* Greek:** λεῖος leios "smooth"...
. - Proellex has completed a number of clinical trials to treat endometriosis and uerine fibroids.
While these SPRMs have been effective for the treatment of uterine fibroids, development of side effects such as endometrial thickening has limited their administration to no longer than three to four months.
Mechanism of action
Synthetic SPRMs differ in chemical structure from the endogenous hormone progesteroneProgesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
, but nevertheless bind to the same progesterone receptor
Progesterone receptor
The progesterone receptor also known as NR3C3 , is an intracellular steroid receptor that specifically binds progesterone...
. In humans, there is only one gene that codes for the receptor, but two splice variants (PR-A and -B) arising from this single gene each with a somewhat different tissue distribution and intrinsic functional activity in response to ligand binding (agonist vs. antagonist). In addition, synthetic SPRMs may have some binding selectivity between the two isoforms, although this is unlikely as the ligand binding domains of the two isoforms are identical.
A more likely origin of the tissue selectivity of SPRMs is what conformational preference these ligands induce in the receptor. The ligand binding domain of the receptor is in equilibrium between two different conformations. The first is an agonist conformation which favors the binding of coactivator
Coactivator (genetics)
A coactivator is a protein that increases gene expression by binding to an activator which contains a DNA binding domain. The coactivator is unable to bind DNA by itself....
proteins which in turn favors upregulation of gene transcription. The second is an antagonistic conformation which in contrast favors the binding of corepressor
Corepressor (genetics)
In molecular genetics, a corepressor is a substance that inhibits the expression of genes. A corepressor downregulates the expression of genes not through direct interaction with a gene promoter , but rather indirectly through interaction with repressor proteins that in turn bind to the...
s and as a consequence down regulation of gene expression. Full agonists such as progesterone which display agonist properties in all tissues, strongly shift the conformational equilibrium in the agonist direction. Conversely full antagonists such as RU-486 strongly shift the equilibrium in the antagonist direction. Finally, the overall ratio of concentrations of coactivator to corepressor may differ in different cell types.
When SPRMs bind to the progesterone receptor, the equilibrium between the two conformational states is more closely balanced and hence more easily perturbed by differences in the cellular environment. In tissues where the concentration of coactivators is higher than corepressors, the excess coactivators drive the equilibrium in the agonist direction. Conversely in tissues where corepressor concentration is higher the equilibrium is driven in the antagonist direction. Hence SPRMs display agonist activity in tissues where coactivators predominate and antagonist activity where corepressors are in excess.
See also
- Selective receptor modulatorSelective receptor modulatorIn the field of pharmacology, a selective receptor modulator or SRM is a type of drug that has different effects in different tissues. A SRM may behave as an agonist in some tissues while as an antagonist in others. Hence selective receptor modulators are sometimes referred to as tissue selective...
- Selective androgen receptor modulatorSelective androgen receptor modulatorSelective androgen receptor modulators or SARMs are a novel class of androgen receptor ligands. They are intended to have the same kind of effects as androgenic drugs like anabolic steroids but be much more selective in...
- Selective estrogen receptor modulatorSelective estrogen receptor modulatorSelective Estrogen Receptor Modulators are a class of compounds that act on the estrogen receptor. A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively...
- Selective glucocorticoid receptor agonistSelective glucocorticoid receptor agonistA selective glucocorticoid receptor agonist , sometimes called a dissociated glucocorticoid receptor agonist , is a type of experimental drug that is designed to share many of the desirable anti-inflammatory and immunosuppressive properties of classical glucocorticoid drugs but with fewer side...