How inverse can a neutral antagonist be? Strategic questions after the rimonabant issue.

Rimonabant is an anti-obesity agent, at the therapeutic level, and a cannabinoid-1 receptor inverse agonist, at the molecular pharmacology level. The drug is currently off the market after psychiatric disorders were observed in some patients. If the adverse effects are attributed to its inverse agonist character, it makes sense to limit the drug discovery space to neutral antagonists. But do neutral antagonists exist? Here, the influence of the sensitivity of the signal transduction machinery on potential neutral antagonist misclassification is modelled. It is proposed that absolute neutral antagonists do not exist, and it is suggested that decisions about the continuity of the compounds in the drug development process be made in a quantitative inverse agonist scale rather than in a qualitative neutral antagonist and inverse agonist classification. (c) 2010 Elsevier Ltd. All rights reserved.