Mixed agonistsantagonists

The development of therapeutically useful mixed AR agonists/antagonists, like the clinically available SERMs for ER, may offer unique therapeutic advantages over their only agonistic counterparts. The steroidal compound mifepristone (RU38486) has partial agonistic and antagonistic actions (Berrevoets etal. 2002). Recently non-steroidal ligands known for better receptor selectivity than steroidal ligands were developed for estrogen, gestagen and androgen receptors.

It was shown previously that hydroxyflutamide, which is a known antiandro-gen in most tissues, may function as a SARM showing effects on IL-6 production by osteoblastic cells, and that its potency depends on their number of functional AR expressed (Hofbauer et al. 1999). The search and validation of mixed agonists/antagonists is still ongoing. The near future will reveal if these molecules are useful for either tissue specific agonistic activity in human disorders like hypogonadism or for tissue-specific antagonistic activities for e.g. treatment of PCa in men or hirsutism in women.

20.5 Key messages

• Selective androgen receptor modulators (SARMs) are ligands for the AR which have mixed agonistic and antagonistic activities.

• Different mechanism are feasible to achieve tissue- and organ-selective androgen action.

• SARMs may be useful to achieve tissue-selective agonistic/antagonistic properties.

• The transformation of the androgen to its metabolites is specific for tissues.

• The AR interacts with DNA as well as with proteins, resulting in altered receptor conformation.

• Comodulators either enhance (coactivator) or repress (corepressor) transcription of target genes.

• The expression of AR and comodulators is specific for tissues and organs.

• Transcriptional reporter assays as well as in vivo test systems are used to discover SARMs and tissue-selective androgens.

• The definition for an ideal tissue-selective androgen depends on the indication.

• Dissociated androgens belong to the classes of steroidal as well as non-steroidal compounds.

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