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Novel retinoids with receptor selectivity and functional selectivity
1Retinoid Research, Department of Biology, Allergan Inc., Irvine, California 92623-9534, USA.
Abstract:
Retinoids mediate a number of physiological pathways through their effects on cellular growth and differentiation. Upon binding to retinoic acid receptors (RARs) and retinoid X receptors (RXRs), retinoids regulate cellular processes by directly modulating the expression of responsive genes. The wide-ranging effects of retinoid action are attributable to two main factors-the ubiquitous distribution of several subtypes and isoforms of RARs and RXRs, and the ability of these receptors to regulate numerous genes upon ligand activation. The broad range of effects mediated by retinoids means not only that they have many potential therapeutic applications but also that non-selective retinoids are associated with a high incidence of adverse effects. The design of retinoids that are receptor-selective and function-selective is a strategy that is proving successful in developing novel retinoids that offer not only good efficacy but also good tolerability. Tazarotene, a receptor-selective retinoid indicated for the topical treatment of psoriasis, is at the forefront of this new generation of retinoids. In the near future, other receptor-selective retinoids may prove useful for the treatment of other dermatological diseases, cancer, and diabetes.
Insights
Retinoids, like retinoic acid, regulate genes via receptors (RARs/RXRs). Selective retinoids offer improved efficacy and tolerability for treating conditions like psoriasis, cancer, and diabetes.
Area of Science:
- Molecular biology
- Pharmacology
- Dermatology
Background:
- Retinoids influence cellular growth and differentiation by binding to retinoic acid receptors (RARs) and retinoid X receptors (RXRs).
- These receptors modulate gene expression, leading to widespread physiological effects due to receptor distribution and gene regulation capabilities.
- Non-selective retinoids have broad therapeutic potential but are linked to significant adverse effects.
Purpose of the Study:
- To explore the development of novel retinoids with improved efficacy and tolerability.
- To highlight the strategy of designing receptor-selective and function-selective retinoids.
- To discuss the potential applications of these advanced retinoids in various diseases.
Main Methods:
- Investigating the mechanism of retinoid action through receptor binding and gene modulation.
- Analyzing the structure-activity relationships of different retinoid compounds.
- Evaluating the efficacy and tolerability of selective retinoids in preclinical and clinical settings.
Main Results:
- Selective retinoids demonstrate targeted therapeutic effects with reduced side effects.
- Tazarotene, a topical retinoid, exemplifies the success of this new generation for psoriasis treatment.
- The development of selective retinoids is a promising strategy for novel therapeutic interventions.
Conclusions:
- Receptor-selective and function-selective retinoids represent a significant advancement in therapeutic design.
- These novel retinoids offer a favorable balance of efficacy and tolerability.
- Future applications are anticipated for dermatological diseases, cancer, and diabetes.