Search for selective antagonists at α1-adrenoreceptors: Neutral or negative antagonism?

In this article the use of competitive antagonists as tools in receptor characterization and classification is discussed. It is pointed out that caution is required in receptor characterization because negative antagonism (inverse agonism) rather than neutral antagonism could play a relevant role. This implies that antagonists should be evaluated not only with regard to their affinity, but also with regard to their ability to affect the equilibrium between the two receptor states, namely active and inactive states. Since affinity and efficacy of a negative antagonist are system dependent the use of negative antagonists as competitive antagonists in receptor characterization may give rise to false differences in receptor subtypes. Finally, this article summarizes recent developments in the design of new α1-adrenoreceptor antagonists which are structurally related to prazosin or WB 4101.