Novel mechanisms of drug action: Functional selectivity at D2 dopamine receptors (a lesson for drug discovery)

Richard B. Mailman, Elaine A. Gay

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Pharmacological dogma teaches that every drug or compound that binds to a receptor has the property of "intrinsic efficacy" (i.e., the ability of that molecule to cause agonist, antagonist, partial agonist, or inverse agonist effects). Although the observed response in any system ("intrinsic activity") can be influenced by many biological factors (e.g., receptor expression level), theory has held that "intrinsic efficacy" is a property of each molecule at a target receptor. Recently, data from many G protein-coupled receptor systems demonstrate that some drugs may have markedly different functional effects acting through a single receptor. This chapter will demonstrate this phenomenon with the dopamine D2 receptor, and show how both model compounds (e.g., dihydrexidine and its select analogs) and the novel atypical antipsychotic drug aripiprazole have function-specific characteristics. These data illustrate that these compounds can cause effects as diverse as pure antagonism versus full agonism solely explicable by their binding to the D2L receptor. These data have led to a new hypothesis called variously "functional selectivity" or "agonist trafficking" that posits that the conformational change induced by non-endogenous ligands for a receptor may cause differential functional activation depending on the G protein, and, possibly, other associated modulating and scaffolding proteins associated with the target receptor. We also provide two examples (N-n-propyldihydrexidine and aripiprazole) showing that functional selectivity in vitro predicts novel behavioral effects in vivo. Not only does the functional selectivity hypothesis provide an explanation for previously contradictory observations, it also opens new horizons for drug discovery. It provides a route to novel drugs targeting only some of the functions modulated by a single receptor, something with implications at both the basic and clinical level.

Original languageEnglish (US)
Pages (from-to)115-126
Number of pages12
JournalMedicinal Chemistry Research
Issue number1-2
StatePublished - Nov 8 2004

All Science Journal Classification (ASJC) codes

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry


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