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Ligands

Sorting good from bad

Nature Reviews Drug Discovery volume 1, page 750 (2002)Cite this article

The authors looked at the α2A-adrenoceptor (α2A-AR), as genetic manipulation of this receptor in mice had shown that it was involved in several responses — both clinically desired (for example, hypotension) and unwanted (for example, sedation). So, they were surprised to find that in heterozygous models (α2A-AR+/− mice) supramaximal doses of α2A-agonists lowered blood pressure without affecting sedation, implying that more than 50% of α2A-AR must be activated to cause sedation.

Limbird and colleagues hypothesized that differing fractional activation of receptors by using partial agonists (or alternatively by administering incremental doses of a full agonist) could produce these selective responses. This idea was supported by the fact that moxonidine (which the authors showed to be a partial agonist in in vitro studies) has no hypotensive effects in α2A-AR-null mice but lowers blood pressure without sedation in wild-type mice.

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References

ORIGINAL RESEARCH PAPER

  1. Tan, C. M., Wilson, M. H. MacMillan, L. B., Kobilka, B. K. & Limbird, L. E. Heterozygous α2A-adrenergic receptor null mice unveil unique therapeutic benefits of partial agonists. Proc. Natl Acad. Sci. USA 99, 12471–12476 (2002)

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FURTHER READING

  1. Kenakin, T. Efficacy at G-protein-coupled receptors. Nature Rev. Drug Discov. 1, 103–110 (2002)

    Article  CAS  Google Scholar 

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Authors
  1. Simon Frantz
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Frantz, S. Sorting good from bad. Nat Rev Drug Discov 1, 750 (2002). https://doi.org/10.1038/nrd932

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  • DOI: https://doi.org/10.1038/nrd932

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