Identification, structure, and agonist design of an androgen receptor
In this international study, the scientists were able to show that one of the adhesion G protein- coupled receptors – GPR133 – is activated by the androgenic steroid hormone 5α-DHT. “This activation can, among other things, increase the contractile force of skeletal muscles, and our study also uses a newly developed, potent activator of this receptor to specifically trigger this effect,” says a co-leader of the study.
Activation of GPR133 by the novel agonist AP503 increases muscle strength without triggering a specific negative effect that is otherwise observed when androgens are administered. For example, increased and prolonged exposure to testosterone can promote the development of prostate cancer, as evidenced by tissue changes in the prostate in mice after only two weeks of androgen administration. This side effect has not yet been observed with AP503.
In addition, the current study uses structural biology methods to elucidate the molecular basis of the interaction between the steroid hormone, the substance AP503 and GPR133. This will allow the activator to be specifically optimised and further developed into a new therapeutic agent. This could lead to the development of new muscle-strengthening drugs with a lower side-effect profile.
The researchers are currently working on several follow-up studies to further investigate the use of AP503 in disease processes and the role of GPR133 in the organism. Here the data were analysed in animal models. Further studies are needed to investigate the applicability of the findings to humans.
