INTRINSIC ACTIVITY AT THE MOLECULAR-LEVEL - ARIENS,E.J. CONCEPT VISUALIZED

The concept of using affinity and intrinsic activity to analyze drug i nteractions with receptors has had a long history in pharmacological s tudies. In the simplest case, the biological response will be proporti onal to the amount of drug bound, i.e. its affinity However, the biolo gical response is also mediated by the ability of a drug when bound to exert its maximum effectiveness. This effectiveness is termed the int rinsic activity Physicochemical processes have been thought to be at t he basis of intrinsic activity Detailed oxygen and solution binding ex periments combined with X-ray crystallographic studies on allosteric e ffecters to hemoglobin demonstrate that these potential drug agents bi nd at the same site in hemoglobin with similar binding constants yet s hift the allosteric equilibrium and the oxygen affinity of the T-struc ture by different degrees. Therefore some of the effecters with simila r binding affinities for the same site exhibit varying degrees of affe ctiveness, i.e. they possess different intrinsic activities. The intri nsic activity of the effector is defined as the ratio of the oxygen af finity constant to the T-state with drug/oxygen affinity constant to t he T-state without drug (K-T+drug)/(K-Tcontrol) The source of the intr insic activity appears to be the ability of the effecters to interact with key residues such as Lys99 alpha at the binding site. These resul ts suggest a general molecular mechanism for allosteric effector modul ation of hemoglobin function that might be of use in other allosteric enzyme systems.